<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/NCT03787303</url>
  </required_header>
  <id_info>
    <org_study_id>2018.08.ST</org_study_id>
    <nct_id>NCT03787303</nct_id>
  </id_info>
  <brief_title>Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma</brief_title>
  <acronym>B-TREUH</acronym>
  <official_title>A Single Arm Phase II Pilot Study of Euthyroid Hypothyroxinemia in Metastatic Breast Carcinoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aultman Health Foundation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Aultman Health Foundation</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Up to one third of breast cancer patients have hypothyroidism or hyperthyroidism. L-thyroxine&#xD;
      (T4), or Synthroid, is the most commonly prescribed agent for the management of&#xD;
      hypothyroidism in the US. However, there are data suggesting that triiodothyronine (T3) may&#xD;
      have benefits in preventing disease progression over l-thyroxine (T4).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      It is estimated that there are approximately 155,000 living with metastatic breast cancer in&#xD;
      the US and the number is estimated to increase over the next years (SEER data). Although&#xD;
      their median survival has improved over the last 2 decades from 17 months to approximately 24&#xD;
      months attributed to newer treatments, there is an ongoing need for additional strategies and&#xD;
      research to improve survival and quality of life.&#xD;
&#xD;
      Many studies have explored the connection between hypothyroidism and hyperthyroidism and&#xD;
      breast cancer with varied results ranging up to one third prevalence. Low Triiodothyronine&#xD;
      (T3) and elevated Thyroid-Stimulating Hormone (TSH) levels have been detected in newly&#xD;
      diagnosed breast cancer patients. Other studies have suggested that some of the common&#xD;
      symptoms reported by breast cancer survivors such as fatigue and depression can be attributed&#xD;
      to subclinical hypothyroidism.&#xD;
&#xD;
      L-thyroxine (T4) is the most commonly prescribed agent for the management of hypothyroidism&#xD;
      in the US. However, there are data suggesting that T4 is a potent pro-oncogenic agent.&#xD;
      Proposed mechanisms include stimulation of mitogenesis, angiogenesis and resistance to&#xD;
      apoptosis, opposition of anti-PDL-1 and radiation effects. It has been postulated that the&#xD;
      avbeta3integrin that is universally expressed on cancer cells harbors a thyroid hormone&#xD;
      receptor and T4 interacts with it.&#xD;
&#xD;
      Triiodothyronine (T3) on the other hand, is significantly less oncogenic and less mitogenic&#xD;
      and is downstream of T4 which is a T3 pro-hormone. Therefore, exogenous supplementation of T3&#xD;
      would decrease the T4 levels creating the desired state of euthyroid hypothyroxinemia.&#xD;
&#xD;
      The rationale of this study is to replace L-thyroxine (T4) with Triiodothyronine (T3) in&#xD;
      hypothyroid patients with metastatic breast carcinoma while they continue to receive standard&#xD;
      systemic therapy, titrating the dose to achieve a state of euthyroid hypothyroxinemia which&#xD;
      is turn would result in a lower risk of disease progression and improved survival by lowering&#xD;
      the concentration of T4.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Relocation of Principal Investigator&#xD;
  </why_stopped>
  <start_date type="Actual">March 1, 2019</start_date>
  <completion_date type="Actual">March 9, 2022</completion_date>
  <primary_completion_date type="Actual">March 9, 2022</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>Triiodothyronine (T3) - IND Exempt</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>N/A (not applicable)</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care</measure>
    <time_frame>12 months</time_frame>
    <description>To prospectively evaluate the progression-free survival in hypothyroid patients with metastatic breast carcinoma who are rendered euthyroid and hypothyroxinemic. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the nadir sum of the longest diameter (SLD) of target lesions, or unequivocal progression (overall level of substantial worsening) in existing non-target lesions, or the appearance of one or more new lesions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients.</measure>
    <time_frame>Study duration, planned was 48 months but actual was 36 months [March 1, 2019 to March 9, 2022] due to premature closure due to planned relocation of the PI.</time_frame>
    <description>To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of Quality of Life Total Score Across Time Using Validated FACT-B Questionnaire</measure>
    <time_frame>Baseline, 3, 6, 9, and 12 months</time_frame>
    <description>Functional Assessment of Cancer Therapy - Breast (FACT-B) Total Score comprised of Physical Well Being (PWB), Social Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), and Breast Cancer Subscale (BCS). Range is 0-148. A higher score indicates higher quality of life. Missing scores were handled by prorating values.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of Energy Level Across Time Using FACT-B Question.</measure>
    <time_frame>Baseline, 3, 6, 9, 12 months</time_frame>
    <description>Functional Assessment of Cancer Therapy - Breast (FACT-B) Lack of energy on 5 point Likert scale as measured on FACT-B Physical Well-being subscale. Score of 0 indicates no lack of energy with score of 4 indicating total lack of energy.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to Achieve Euthyroid Hypothyroxinemia State</measure>
    <time_frame>Number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value for each participant, assessed up to 12 months</time_frame>
    <description>To study the average time required to achieve euthyroid hypothyroxinemia state in qualifying patients. Thyroid function laboratory testing was performed at baseline and then at every 4 weekly intervals until 12 weeks then every 3 monthly thereafter, unless thyroid-stimulating hormone (TSH) was abnormal. If a normal TSH level was not achieved by the 12 week visit, repeat TSH measurements were ordered every 4-6 weeks until the TSH value was within the laboratory normal reference range. Initial euthyroid state defined by number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">7</enrollment>
  <condition>Metastatic Breast Cancer</condition>
  <condition>Thyroid Dysfunction</condition>
  <arm_group>
    <arm_group_label>Triiodothyronine (T3)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Triiodothyronine (T3)</intervention_name>
    <description>Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
    <arm_group_label>Triiodothyronine (T3)</arm_group_label>
    <other_name>liothyronine sodium</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater than or equal to 18&#xD;
&#xD;
          -  Male or female with diagnosis of metastatic breast carcinoma and documented history of&#xD;
             hypothyroidism .&#xD;
&#xD;
          -  TSH level within normal range at baseline&#xD;
&#xD;
          -  Life expectancy estimated &gt; 3 months&#xD;
&#xD;
          -  Ability and willingness to provide informed consent&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Life expectancy estimated to be less than 3 months&#xD;
&#xD;
          -  Is currently pregnant or intends to become pregnant during the duration of the study&#xD;
&#xD;
          -  Active angina, New York Heart Association (NYHA) advanced [Class III/IV] congestive&#xD;
             heart failure, or uncontrolled cardiac arrhythmia within 6 months of enrollment&#xD;
&#xD;
          -  History of thyrotoxicosis&#xD;
&#xD;
          -  History of adrenal insufficiency&#xD;
&#xD;
          -  Hypersensitivity to any active or extraneous constituents in Triiodothyronine&#xD;
             (T3)/liothyronine sodium&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>105 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Shruti Trehan, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Aultman Health Foundation</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Aultman Medical Group Hematology and Oncology</name>
      <address>
        <city>Canton</city>
        <state>Ohio</state>
        <zip>44710</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2022</verification_date>
  <study_first_submitted>December 12, 2018</study_first_submitted>
  <study_first_submitted_qc>December 21, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 26, 2018</study_first_posted>
  <results_first_submitted>March 17, 2022</results_first_submitted>
  <results_first_submitted_qc>May 11, 2022</results_first_submitted_qc>
  <results_first_posted type="Actual">May 13, 2022</results_first_posted>
  <last_update_submitted>May 11, 2022</last_update_submitted>
  <last_update_submitted_qc>May 11, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">May 13, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Aultman Health Foundation</investigator_affiliation>
    <investigator_full_name>Shruti Trehan MD</investigator_full_name>
    <investigator_title>Shruti Trehan MD</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>April 8, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT03787303/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 14, 2022</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT03787303/SAP_003.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>October 16, 2020</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/03/NCT03787303/ICF_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>7 participants from one local medical oncology practice were enrolled between March 1, 2019 and March 9, 2022.</recruitment_details>
      <pre_assignment_details>All enrolled participants underwent a four day washout period of L-thyroxine (T4) prior to Triiodothyronine (T3) initiation. There were no enrolled participants who were excluded from the study.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Triiodothyronine (T3)</title>
          <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="7"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Premature Termination of Study</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Triiodothyronine (T3)</title>
          <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="7"/>
          </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="63.7" spread="13.52"/>
                  </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="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </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="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Duration of time since diagnosis of metastatic disease</title>
          <units>months</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="62.1" spread="79.52"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care</title>
        <description>To prospectively evaluate the progression-free survival in hypothyroid patients with metastatic breast carcinoma who are rendered euthyroid and hypothyroxinemic. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the nadir sum of the longest diameter (SLD) of target lesions, or unequivocal progression (overall level of substantial worsening) in existing non-target lesions, or the appearance of one or more new lesions.</description>
        <time_frame>12 months</time_frame>
        <population>Last enrolled subject was only able to be followed for 9 months due to early termination of study. Subject not included in primary outcome measure.</population>
        <group_list>
          <group group_id="O1">
            <title>Triiodothyronine (T3)</title>
            <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care</title>
          <description>To prospectively evaluate the progression-free survival in hypothyroid patients with metastatic breast carcinoma who are rendered euthyroid and hypothyroxinemic. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the nadir sum of the longest diameter (SLD) of target lesions, or unequivocal progression (overall level of substantial worsening) in existing non-target lesions, or the appearance of one or more new lesions.</description>
          <population>Last enrolled subject was only able to be followed for 9 months due to early termination of study. Subject not included in primary outcome measure.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients.</title>
        <description>To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice.</description>
        <time_frame>Study duration, planned was 48 months but actual was 36 months [March 1, 2019 to March 9, 2022] due to premature closure due to planned relocation of the PI.</time_frame>
        <population>Outcome was number of practice patients with both metastatic breast cancer and hypothyroidism. Of the 26 identified, 7 patients consented to enroll on the study.</population>
        <group_list>
          <group group_id="O1">
            <title>Triiodothyronine (T3)</title>
            <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients.</title>
          <description>To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice.</description>
          <population>Outcome was number of practice patients with both metastatic breast cancer and hypothyroidism. Of the 26 identified, 7 patients consented to enroll on the study.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="126"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="26"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Measurement of Quality of Life Total Score Across Time Using Validated FACT-B Questionnaire</title>
        <description>Functional Assessment of Cancer Therapy - Breast (FACT-B) Total Score comprised of Physical Well Being (PWB), Social Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), and Breast Cancer Subscale (BCS). Range is 0-148. A higher score indicates higher quality of life. Missing scores were handled by prorating values.</description>
        <time_frame>Baseline, 3, 6, 9, and 12 months</time_frame>
        <population>Of the 7 subjects enrolled only 5 of the patients completed Quality of Life FACT-B questionnaires for all five timepoint. Two subjects did not complete the 12 months surveys due to death or premature study termination.</population>
        <group_list>
          <group group_id="O1">
            <title>Triiodothyronine (T3)</title>
            <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
          </group>
        </group_list>
        <measure>
          <title>Measurement of Quality of Life Total Score Across Time Using Validated FACT-B Questionnaire</title>
          <description>Functional Assessment of Cancer Therapy - Breast (FACT-B) Total Score comprised of Physical Well Being (PWB), Social Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), and Breast Cancer Subscale (BCS). Range is 0-148. A higher score indicates higher quality of life. Missing scores were handled by prorating values.</description>
          <population>Of the 7 subjects enrolled only 5 of the patients completed Quality of Life FACT-B questionnaires for all five timepoint. Two subjects did not complete the 12 months surveys due to death or premature study termination.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="114" spread="24.56"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At 3 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="114" spread="16.80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At 6 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="116" spread="20.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At 9 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="112" spread="26.92"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>At 12 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="110" spread="23.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Measurement of Energy Level Across Time Using FACT-B Question.</title>
        <description>Functional Assessment of Cancer Therapy - Breast (FACT-B) Lack of energy on 5 point Likert scale as measured on FACT-B Physical Well-being subscale. Score of 0 indicates no lack of energy with score of 4 indicating total lack of energy.</description>
        <time_frame>Baseline, 3, 6, 9, 12 months</time_frame>
        <population>Of the 7 subjects enrolled only 5 of the patients completed Quality of Life FACT-B questionnaires for all five timepoint. Two subjects did not complete the 12 months surveys due to death or premature study termination.</population>
        <group_list>
          <group group_id="O1">
            <title>Triiodothyronine (T3)</title>
            <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
          </group>
        </group_list>
        <measure>
          <title>Measurement of Energy Level Across Time Using FACT-B Question.</title>
          <description>Functional Assessment of Cancer Therapy - Breast (FACT-B) Lack of energy on 5 point Likert scale as measured on FACT-B Physical Well-being subscale. Score of 0 indicates no lack of energy with score of 4 indicating total lack of energy.</description>
          <population>Of the 7 subjects enrolled only 5 of the patients completed Quality of Life FACT-B questionnaires for all five timepoint. Two subjects did not complete the 12 months surveys due to death or premature study termination.</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.9" spread="1.07"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.4" spread="1.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>6 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" spread="1.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>9 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="7"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.0" spread="1.53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>12 months</title>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="O1" value="5"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.6" spread="1.14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Achieve Euthyroid Hypothyroxinemia State</title>
        <description>To study the average time required to achieve euthyroid hypothyroxinemia state in qualifying patients. Thyroid function laboratory testing was performed at baseline and then at every 4 weekly intervals until 12 weeks then every 3 monthly thereafter, unless thyroid-stimulating hormone (TSH) was abnormal. If a normal TSH level was not achieved by the 12 week visit, repeat TSH measurements were ordered every 4-6 weeks until the TSH value was within the laboratory normal reference range. Initial euthyroid state defined by number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value.</description>
        <time_frame>Number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value for each participant, assessed up to 12 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Triiodothyronine (T3)</title>
            <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Achieve Euthyroid Hypothyroxinemia State</title>
          <description>To study the average time required to achieve euthyroid hypothyroxinemia state in qualifying patients. Thyroid function laboratory testing was performed at baseline and then at every 4 weekly intervals until 12 weeks then every 3 monthly thereafter, unless thyroid-stimulating hormone (TSH) was abnormal. If a normal TSH level was not achieved by the 12 week visit, repeat TSH measurements were ordered every 4-6 weeks until the TSH value was within the laboratory normal reference range. Initial euthyroid state defined by number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value.</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="7"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="59.6" spread="50.64"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Adverse event data was collected for each subject at every 3 monthly visit and is reported as below. Attribution or etiology under comments below. Study period was 12 months (9 months for last patient due to premature termination of study)</time_frame>
      <desc>112/124 - 88.7% of adverse events were deemed to be related to underlying metastatic breast cancer and/or treatment thereof.&#xD;
0 events reported definitely related to the study drug 14/124 -11.3% events reported as possible or probably related to the study drug Cause of mortality reported due to metastatic breast cancer.</desc>
      <group_list>
        <group group_id="E1">
          <title>Triiodothyronine (T3)</title>
          <description>Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 &lt; 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).&#xD;
Triiodothyronine (T3): Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (version 5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>ascites</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Cellulitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Pleural effusion</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (version 5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Palpitations</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Endocrine disorder: Cold intolerance</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Watering eyes</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorder: Other hemoccult positive</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders: Other - Gastroenteritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Mucositis Oral</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Tooth loss</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="4" subjects_affected="4" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Bronchial infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>White blood cell count decreased</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decrease</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Arthalgia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Memory Impairment</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Anosmia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Blood urea nitrogen increase</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Creatinine increase</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Rhinorrhea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Nail changes</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Skin disorder other: Contact dermatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Skin disorder: Other - Chest wall redness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Pruritis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Skin disorder: Other-onycholysis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Nail peeling</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="7" subjects_affected="5" subjects_at_risk="7"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="7"/>
              </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>
    <limitations_and_caveats>Limitation is small sample size due to pandemic affecting clinical trial accrual. A larger sample is needed to adequately answer the research question.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Shruti Trehan MD</name_or_title>
      <organization>Aultman Hospital</organization>
      <phone>3303634162</phone>
      <email>trehanshruti4@gmail.com</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/NCT03787303
org study id: 2018.08.ST
nct id: NCT03787303
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
Up to one third of breast cancer patients have hypothyroidism or hyperthyroidism. L-thyroxine
      (T4), or Synthroid, is the most commonly prescribed agent for the management of
      hypothyroidism in the US. However, there are data suggesting that triiodothyronine (T3) may
      have benefits in preventing disease progression over l-thyroxine (T4).
It is estimated that there are approximately 155,000 living with metastatic breast cancer in
      the US and the number is estimated to increase over the next years (SEER data). Although
      their median survival has improved over the last 2 decades from 17 months to approximately 24
      months attributed to newer treatments, there is an ongoing need for additional strategies and
      research to improve survival and quality of life.

      Many studies have explored the connection between hypothyroidism and hyperthyroidism and
      breast cancer with varied results ranging up to one third prevalence. Low Triiodothyronine
      (T3) and elevated Thyroid-Stimulating Hormone (TSH) levels have been detected in newly
      diagnosed breast cancer patients. Other studies have suggested that some of the common
      symptoms reported by breast cancer survivors such as fatigue and depression can be attributed
      to subclinical hypothyroidism.

      L-thyroxine (T4) is the most commonly prescribed agent for the management of hypothyroidism
      in the US. However, there are data suggesting that T4 is a potent pro-oncogenic agent.
      Proposed mechanisms include stimulation of mitogenesis, angiogenesis and resistance to
      apoptosis, opposition of anti-PDL-1 and radiation effects. It has been postulated that the
      avbeta3integrin that is universally expressed on cancer cells harbors a thyroid hormone
      receptor and T4 interacts with it.

      Triiodothyronine (T3) on the other hand, is significantly less oncogenic and less mitogenic
      and is downstream of T4 which is a T3 pro-hormone. Therefore, exogenous supplementation of T3
      would decrease the T4 levels creating the desired state of euthyroid hypothyroxinemia.

      The rationale of this study is to replace L-thyroxine (T4) with Triiodothyronine (T3) in
      hypothyroid patients with metastatic breast carcinoma while they continue to receive standard
      systemic therapy, titrating the dose to achieve a state of euthyroid hypothyroxinemia which
      is turn would result in a lower risk of disease progression and improved survival by lowering
      the concentration of T4.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Triiodothyronine (T3) - IND Exempt
primary purpose: Treatment
masking: None (Open Label)
masking description: N/A (not applicable)
measure: Number of Participants With Progression-free Survival at 12 Months Based Upon Clinical and Radiological Assessments Completed as Part of Routine Care
time frame: 12 months
description: To prospectively evaluate the progression-free survival in hypothyroid patients with metastatic breast carcinoma who are rendered euthyroid and hypothyroxinemic. Progression is defined using Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the nadir sum of the longest diameter (SLD) of target lesions, or unequivocal progression (overall level of substantial worsening) in existing non-target lesions, or the appearance of one or more new lesions.
measure: Number of Patients With Both Metastatic Breast Cancer and Hypothyroidism in All Screened Patients.
time frame: Study duration, planned was 48 months but actual was 36 months [March 1, 2019 to March 9, 2022] due to premature closure due to planned relocation of the PI.
description: To quantitate the prevalence of hypothyroidism in metastatic breast cancer patients at a community oncology practice.
measure: Measurement of Quality of Life Total Score Across Time Using Validated FACT-B Questionnaire
time frame: Baseline, 3, 6, 9, and 12 months
description: Functional Assessment of Cancer Therapy - Breast (FACT-B) Total Score comprised of Physical Well Being (PWB), Social Well Being (SWB), Emotional Well Being (EWB), Functional Well Being (FWB), and Breast Cancer Subscale (BCS). Range is 0-148. A higher score indicates higher quality of life. Missing scores were handled by prorating values.
measure: Measurement of Energy Level Across Time Using FACT-B Question.
time frame: Baseline, 3, 6, 9, 12 months
description: Functional Assessment of Cancer Therapy - Breast (FACT-B) Lack of energy on 5 point Likert scale as measured on FACT-B Physical Well-being subscale. Score of 0 indicates no lack of energy with score of 4 indicating total lack of energy.
measure: Time to Achieve Euthyroid Hypothyroxinemia State
time frame: Number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value for each participant, assessed up to 12 months
description: To study the average time required to achieve euthyroid hypothyroxinemia state in qualifying patients. Thyroid function laboratory testing was performed at baseline and then at every 4 weekly intervals until 12 weeks then every 3 monthly thereafter, unless thyroid-stimulating hormone (TSH) was abnormal. If a normal TSH level was not achieved by the 12 week visit, repeat TSH measurements were ordered every 4-6 weeks until the TSH value was within the laboratory normal reference range. Initial euthyroid state defined by number of days between initiation of triiodothyronine (T3) and documentation of first normal TSH value.
arm group label: Triiodothyronine (T3)
arm group type: Experimental
description: Following discontinuation of L-thyroxine (T4), triiodothyronine (T3) will be initiated at a 3:1 ratio. The dose will be titrated by the investigator to maintain levels of free T4 < 50% of normal range while maintaining a euthyroid state. Triiodothyronine (T3) tablets for oral administration will be prescribed once or twice daily depending on the total dose. Treatment duration will be approximately 9 months during which time the subjects will continue to be treated and monitored as usual for their metastatic breast cancer. During the study period and at the conclusion of the study period, there will be continuous evaluations of the disease status and thyroid status with the option of resuming the original thyroid replacement or continuation of the triiodothyronine (T3).
intervention type: Drug
intervention name: Triiodothyronine (T3)
description: Participants will have their L-thyroxine (T4) discontinued and Triiodothyronine (T3)/liothyronine sodium initiated at 3: 1 and titrated.
arm group label: Triiodothyronine (T3)
other name: liothyronine sodium
criteria: 
gender: All
minimum age: 18 Years
maximum age: 105 Years
healthy volunteers: No
last name: Shruti Trehan, MD
role: Principal Investigator
affiliation: Aultman Health Foundation
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Aultman Health Foundation
investigator full name: Shruti Trehan MD
investigator title: Shruti Trehan MD
mesh term: Breast Neoplasms
provided document: 
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Limitation is small sample size due to pandemic affecting clinical trial accrual. A larger sample is needed to adequately answer the research question.
point of contact: 