<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/NCT02186015</url>
  </required_header>
  <id_info>
    <org_study_id>206519</org_study_id>
    <nct_id>NCT02186015</nct_id>
  </id_info>
  <brief_title>Safety, Feasibility and Efficacy of Vitamin D Supplementation in Women With Metastatic Breast Cancer (SAFE-D)</brief_title>
  <acronym>SAFE-D</acronym>
  <official_title>Safety, Feasibility and Efficacy of Vitamin D Supplementation in Women With Metastatic Breast Cancer (SAFE-D)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Loyola University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Loyola University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Several clinical trials are underway to investigate if variable forms of vitamin&#xD;
      D (D2 vs. D3) prescribed at different doses (10,000-50,000 IUs/week) can improve the&#xD;
      side-effects associated with treatment for estrogen receptor positive (ER+) breast cancer,&#xD;
      specifically aromatase inhibitors (AIs.) Presumably for generalizability and potential safety&#xD;
      purposes, these trials predominantly exclude women with metastatic breast cancer (MBC); a&#xD;
      rapidly expanding sector of the cancer survivor population who experience significant&#xD;
      treatment-related side-effects. Evaluation of the safety of vitamin D3 supplementation is&#xD;
      crucial since supplementation can lead to high calcium and importantly, in lab studies have&#xD;
      shown that vitamin D3 affects a gene that increases estrogen production. To assure that&#xD;
      vitamin D3 does not affect the clinical effects of anti-estrogen therapies, the effect of&#xD;
      vitamin D3 supplements on estrogen production requires an evaluation that further explores&#xD;
      and defines its potential role in symptom management for this population.&#xD;
&#xD;
      Objectives: This pilot study will evaluate the feasibility of vitamin D3 supplementation in&#xD;
      women with MBC, providing much needed data on the preliminary safety and efficacy of this&#xD;
      treatment in this patient population. This study will determine: 1) if weekly supplementation&#xD;
      of high dose vitamin D3 increases serum vitamin D levels without adverse effects related to&#xD;
      such therapy (primary aim); 2) the effects of vitamin D3 supplementation on symptom&#xD;
      management (secondary aim); and 3) if vitamin D3 supplementation is associated with improved&#xD;
      inflammation (exploratory aim.)&#xD;
&#xD;
      Methods: This is an 8 week &quot;proof of concept&quot; study to monitor laboratory parameters and to&#xD;
      assess potential effects on short-term outcomes. Adult, female patients (&gt;=18 years) with ER+&#xD;
      MBC (Stage IV) of any race/ethnicity and a history of vitamin D &lt; 30 mg/dl will be recruited&#xD;
      from within and around LUMC. Following current clinical practice guidelines, eligible&#xD;
      participants will receive 50,000 IUs of vitamin D3 weekly for 8 weeks. Laboratory values,&#xD;
      muscle function and inflammation will be examined pre- and post-supplementation, while&#xD;
      symptoms will be assessed at baseline, 4 and 8 weeks post-supplementation. We will assess if&#xD;
      increases in vitamin D are associated with clinically significant improvements in symptoms&#xD;
      and QOL, and decreased inflammation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Aims&#xD;
&#xD;
      Several clinical trials are underway to investigate if vitamin D2 or D3 provided at various&#xD;
      doses (10,000-50,000 IUs/week) can improve the side-effects associated with anti-estrogen&#xD;
      therapies, specifically aromatase inhibitors (AIs). However, these current trials use&#xD;
      variable forms of vitamin D and predominantly include women with Stage I-III disease,&#xD;
      excluding women with metastatic breast cancer. Evaluation of the safety of vitamin D3&#xD;
      supplementation is crucial since supplementation can lead to hypercalcemia and importantly,&#xD;
      in vitro studies have shown that vitamin D3 influences the transcription of a gene that&#xD;
      increases estrogen production.27,28 To assure that vitamin D3 does not abrogate the clinical&#xD;
      effects of anti-estrogen therapies, the effect of vitamin D3 supplementation on estrogen&#xD;
      production requires evaluation. Therefore, the overarching goal of this pilot study is to&#xD;
      evaluate the safety, feasibility and efficacy of vitamin D3 supplementation in women with&#xD;
      MBC. We will address and test the following aims and hypotheses, respectively:&#xD;
&#xD;
      Aim 1: To determine if weekly supplementation of 50,000 IUs of vitamin D3 raises serum levels&#xD;
      of 25(OH)D to &gt;30 mg/dl without adverse effects.&#xD;
&#xD;
      Hypothesis 1: Women who are compliant with vitamin D3 supplementation, as evidenced by&#xD;
      normalization (&gt;30 mg/dl) or increases in their serum 25(OH)D levels, will not experience&#xD;
      significant changes in serum calcium, parathyroid hormone or serum estradiol levels.&#xD;
&#xD;
      Aim 2: To determine the effect of vitamin D3 supplementation on symptom management.&#xD;
&#xD;
      Hypothesis 2: Women who achieve serum concentrations of 25 (OH)D ≥30 mg/dl or experience&#xD;
      significant increases in 25(OH)D will exhibit improvements in pain, fatigue, sleep, mood,&#xD;
      muscle function and overall quality of life.&#xD;
&#xD;
      Exploratory Aim: To explore the mechanistic effects of vitamin D3 supplementation on&#xD;
      inflammatory markers and its potential association with symptom management.&#xD;
&#xD;
      Summary: Evidence from studies involving early stage breast cancer participants confirms that&#xD;
      musculoskeletal pain, endocrine related symptoms and mood disturbances are commonly&#xD;
      associated with breast cancer treatment, particularly hormone deprivation therapies. The high&#xD;
      prevalence of vitamin D deficiency/insufficiency among breast cancer survivors is well&#xD;
      accepted and further hypothesized to aggravate treatment-related side effects, particularly&#xD;
      arthralgias. Women with MBC are excluded from the majority of on-going vitamin D&#xD;
      supplementation trials for safety and generalizability purposes. However, novel therapies are&#xD;
      continuing to improve and prolong the lives of these women, resulting in a rapidly expansive&#xD;
      group of breast cancer survivors. While vitamin D supplementation is prescribed to correct an&#xD;
      underlying nutrient deficiency in the clinical context of preserving bone health, emerging&#xD;
      evidence suggests it may have more systemic effects. Thus, vitamin D&#xD;
      repletion/supplementation has profound potential implications for women with MBC, whose&#xD;
      primary goal of treatment is to minimize the side-effects of treatment in support of optimal&#xD;
      quality of life. This study reflects a highly innovative, yet simple therapy that could&#xD;
      ultimately provide these survivors with a much needed evidence-based supportive care&#xD;
      strategies.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>February 2015</start_date>
  <completion_date type="Actual">November 9, 2017</completion_date>
  <primary_completion_date type="Actual">March 8, 2017</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Serum 25(OH)D</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Change in laboratory serum value of 25(OH)D at 8 weeks post-supplementation for participants who received weekly supplementation of 50,000 IUs of vitamin D3. Change is expressed as laboratory serum value of 25(OH)D at 8 weeks minus baseline. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Worst Pain Rating From the Beck Pain Scale</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Assessment of pain using the Beck Pain Scale at weeks 0 and 8. This is a Likert scale item where a score of 0 corresponds to no pain and a score of 10 corresponds to worst pain. Change is calculated as the worst pain rating at 8 weeks minus the worst pain rating at 0 weeks.Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Fatigue</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Assessment of fatigue using the Piper Fatigue Scale at weeks 0 and 8. The Piper Fatigue Scale is the average of 22 numeric items, with higher scores indicating greater fatigue [range of scores: 0-10]. Change is calculated as the fatigue score at 8 weeks minus fatigue score at 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Mood</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Assessment of mood using the Patient Health Questionnaire 8 (PHQ-8) at weeks 0 and 8. The PHQ-8 ranges from 0-24 with higher scores indicating more distress. Change was assessed as PHQ-8 score at 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Muscle Function</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Assessment of muscle function using a hand dynamometer at weeks 0 and 8. Change in dominant handgrip strength in kilograms was calculated as 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Sleep Quality Assessment</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Assessment of sleep using the Pittsburgh Sleep Quality Index (PSQI) at weeks 0 and 8. Scores range from 0-21 with higher scores indicating poorer sleep quality. Change was calculated as week 8 minus week 0 PSQI. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Functional Assessment of Cancer Therapy-breast</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Assessment of quality of life using the functional assessment of cancer therapy-breast symptoms at weeks 0 and 8. Scores range from 0-40 with higher scores indicating better quality of life.&#xD;
Change was calculated as week 8 score minus week 0 score. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Functional Assessment of Cancer Therapy-endocrine</measure>
    <time_frame>0, 8 weeks</time_frame>
    <description>Assessment of quality of life using the functional assessment of cancer therapy- endocrine symptoms at weeks 0 and 8. Scores range from 0-76 with higher scores indicating better quality of life. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">43</enrollment>
  <condition>Adult Women</condition>
  <condition>Metastatic Breast Cancer</condition>
  <condition>Estrogen Receptor Positive</condition>
  <arm_group>
    <arm_group_label>Cholecalciferol</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Vitamin D sufficient</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>All participants were ineligible for the intervention due to sufficient serum 25(OH)D levels at screening/baseline.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cholecalciferol</intervention_name>
    <description>Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
    <arm_group_label>Cholecalciferol</arm_group_label>
    <other_name>Vitamin D3</other_name>
    <other_name>Vitamin D</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Metastatic breast cancer (Stage IV)&#xD;
&#xD;
          2. Histologically confirmed estrogen receptor positive disease&#xD;
&#xD;
          3. Female&#xD;
&#xD;
          4. Serum 25(OH) &lt;30 ng/ml&#xD;
&#xD;
          5. Age ≥ 18 years&#xD;
&#xD;
          6. Pre or post-menopausal&#xD;
&#xD;
          7. ECOG Performance status 0-2&#xD;
&#xD;
          8. Adequate organ function as defined as GFR&gt; 30 mls/min and serum calcium ≤ 10.4 mg/dl&#xD;
&#xD;
          9. Any race/ethnicity&#xD;
&#xD;
         10. English speaking&#xD;
&#xD;
         11. No changes to MBC treatments within 30 days of enrollment and/or deemed clinically&#xD;
             stable by their treating physician&#xD;
&#xD;
         12. Willingness to sign a written informed consent and complete questionnaires&#xD;
&#xD;
         13. Cease ingestion of vitamin D supplementation not study related&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Women with Stage I-III breast cancer&#xD;
&#xD;
          2. Serum 25(OH)D levels ≥ 30 ng/ml&#xD;
&#xD;
          3. Untreated CNS involvement&#xD;
&#xD;
          4. History of kidney stones&#xD;
&#xD;
          5. History of renal failure&#xD;
&#xD;
          6. History of hyperparathyroidism&#xD;
&#xD;
          7. History of hypersensitivity to vitamin D&#xD;
&#xD;
          8. Non-English speaking&#xD;
&#xD;
          9. Currently pregnant or lactating, or anticipating pregnancy&#xD;
&#xD;
         10. Unwilling to cease ingestion of calcium supplements (&gt;1000 mg/d)&#xD;
&#xD;
         11. Unwilling or unable to complete informed consent or study questionnaires&#xD;
&#xD;
         12. Psychiatric or other clinical conditions that preclude study compliance&#xD;
&#xD;
         13. Other important medical or safety considerations at the discretion of the investigator&#xD;
             and/or study physician, including non-compliance with the study therapy or other&#xD;
             activities&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Patricia M Sheean, Ph.D., R.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Loyola University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Loyola University Medical Center</name>
      <address>
        <city>Maywood</city>
        <state>Illinois</state>
        <zip>60153</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
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  <verification_date>May 2021</verification_date>
  <study_first_submitted>July 7, 2014</study_first_submitted>
  <study_first_submitted_qc>July 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 10, 2014</study_first_posted>
  <results_first_submitted>September 15, 2020</results_first_submitted>
  <results_first_submitted_qc>May 12, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">May 14, 2021</results_first_posted>
  <last_update_submitted>May 12, 2021</last_update_submitted>
  <last_update_submitted_qc>May 12, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">May 14, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Loyola University</investigator_affiliation>
    <investigator_full_name>Patricia Sheean</investigator_full_name>
    <investigator_title>Research Associate</investigator_title>
  </responsible_party>
  <keyword>Metastatic Breast Cancer</keyword>
  <keyword>MBC</keyword>
  <keyword>Vitamin D Supplementation</keyword>
  <keyword>Symptom Management</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Breast Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Vitamin D</mesh_term>
    <mesh_term>Ergocalciferols</mesh_term>
    <mesh_term>Cholecalciferol</mesh_term>
    <mesh_term>Vitamins</mesh_term>
  </intervention_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>November 1, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/15/NCT02186015/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>November 14, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/15/NCT02186015/SAP_001.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>December 5, 2014</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/15/NCT02186015/ICF_002.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Participants were recruited from a single cancer center and required to be: 1) &gt;18 years of age, 2) English speaking, 3) at a performance status of 0-2, 4) receiving treatment for histologically confirmed ER+ metastatic BC, and 5) clinically stable as judged by their medical oncologist.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Cholecalciferol</title>
          <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.&#xD;
Cholecalciferol: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
        </group>
        <group group_id="P2">
          <title>No Cholecalciferol</title>
          <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="31"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Physician Decision</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Cholecalciferol</title>
          <description>Enrolled women with serum 25 (OH)D less than 30 ng/ml received 50,000 IUs weekly supplementation of cholecalciferol for 8 weeks</description>
        </group>
        <group group_id="B2">
          <title>No Cholecalciferol</title>
          <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="11"/>
            <count group_id="B2" value="31"/>
            <count group_id="B3" value="42"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57" lower_limit="46" upper_limit="64"/>
                    <measurement group_id="B2" value="63" lower_limit="56" upper_limit="70"/>
                    <measurement group_id="B3" value="62" lower_limit="53" upper_limit="68"/>
                  </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="11"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Race/Ethnicity</title>
              <category_list>
                <category>
                  <title>Non-Hispanic White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="26"/>
                    <measurement group_id="B3" value="31"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Hispanic</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Other</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <description>Midwest United States</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="31"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Employment status</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Paid full- or part-time work</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Retired without disability</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Retired with disability</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unemployed</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Body mass index</title>
          <units>kg/m^2</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="27.3" lower_limit="25.3" upper_limit="40.1"/>
                    <measurement group_id="B2" value="27.8" lower_limit="23.7" upper_limit="33.2"/>
                    <measurement group_id="B3" value="27.5" lower_limit="24.1" upper_limit="33.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Stage IV at diagnosis</title>
          <description>Metastatic breast cancer at diagnosis</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="12"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="30"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Duration of metastatic breast cancer</title>
          <units>months</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7" lower_limit="3" upper_limit="14"/>
                    <measurement group_id="B2" value="19" lower_limit="5" upper_limit="45"/>
                    <measurement group_id="B3" value="13" lower_limit="5" upper_limit="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Metastatic sites</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>1 or 2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="25"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Greater than 2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Eastern Cooperative Oncology Group</title>
          <description>The Eastern Cooperative Oncology Group Performance status describes patients' level of functioning, where higher scores indicate lower levels of functioning.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>0</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="11"/>
                    <measurement group_id="B3" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>1</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="25"/>
                  </measurement_list>
                </category>
                <category>
                  <title>2</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Radiation therapy for metastates</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Yes</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
                <category>
                  <title>No</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                    <measurement group_id="B2" value="21"/>
                    <measurement group_id="B3" value="29"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Surgery for breast cancer</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>None</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Lumpectomy</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="14"/>
                    <measurement group_id="B3" value="18"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Mastectomy</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Serum 25(OH)D</title>
          <units>ng/ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17" lower_limit="13" upper_limit="26"/>
                    <measurement group_id="B2" value="38" lower_limit="34" upper_limit="44"/>
                    <measurement group_id="B3" value="34" lower_limit="29" upper_limit="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in Serum 25(OH)D</title>
        <description>Change in laboratory serum value of 25(OH)D at 8 weeks post-supplementation for participants who received weekly supplementation of 50,000 IUs of vitamin D3. Change is expressed as laboratory serum value of 25(OH)D at 8 weeks minus baseline. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did not have laboratory serum value of 25(OH)D at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>Enrolled women received 50,000 IUs weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Serum 25(OH)D</title>
          <description>Change in laboratory serum value of 25(OH)D at 8 weeks post-supplementation for participants who received weekly supplementation of 50,000 IUs of vitamin D3. Change is expressed as laboratory serum value of 25(OH)D at 8 weeks minus baseline. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did not have laboratory serum value of 25(OH)D at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>ng/ml</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32" lower_limit="22" upper_limit="40"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in serum 25(OH)D from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A Wilcoxon signed rank test was performed.</non_inferiority_desc>
            <p_value>&lt;0.01</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Worst Pain Rating From the Beck Pain Scale</title>
        <description>Assessment of pain using the Beck Pain Scale at weeks 0 and 8. This is a Likert scale item where a score of 0 corresponds to no pain and a score of 10 corresponds to worst pain. Change is calculated as the worst pain rating at 8 weeks minus the worst pain rating at 0 weeks.Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did not have laboratory serum value of 25(OH)D at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.&#xD;
Cholecalciferol: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Worst Pain Rating From the Beck Pain Scale</title>
          <description>Assessment of pain using the Beck Pain Scale at weeks 0 and 8. This is a Likert scale item where a score of 0 corresponds to no pain and a score of 10 corresponds to worst pain. Change is calculated as the worst pain rating at 8 weeks minus the worst pain rating at 0 weeks.Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did not have laboratory serum value of 25(OH)D at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="-3" upper_limit="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in worst pain rating from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <non_inferiority_desc>A Wilcoxon signed rank test was performed.</non_inferiority_desc>
            <p_value>0.24</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Fatigue</title>
        <description>Assessment of fatigue using the Piper Fatigue Scale at weeks 0 and 8. The Piper Fatigue Scale is the average of 22 numeric items, with higher scores indicating greater fatigue [range of scores: 0-10]. Change is calculated as the fatigue score at 8 weeks minus fatigue score at 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did not have assessment of fatigue at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>Enrolled women received 50,000 IUs weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Fatigue</title>
          <description>Assessment of fatigue using the Piper Fatigue Scale at weeks 0 and 8. The Piper Fatigue Scale is the average of 22 numeric items, with higher scores indicating greater fatigue [range of scores: 0-10]. Change is calculated as the fatigue score at 8 weeks minus fatigue score at 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did not have assessment of fatigue at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.5" lower_limit="-1.7" upper_limit="0.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in fatigue score from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.09</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Mood</title>
        <description>Assessment of mood using the Patient Health Questionnaire 8 (PHQ-8) at weeks 0 and 8. The PHQ-8 ranges from 0-24 with higher scores indicating more distress. Change was assessed as PHQ-8 score at 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did not have assessment of mood at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.&#xD;
Cholecalciferol: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Mood</title>
          <description>Assessment of mood using the Patient Health Questionnaire 8 (PHQ-8) at weeks 0 and 8. The PHQ-8 ranges from 0-24 with higher scores indicating more distress. Change was assessed as PHQ-8 score at 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did not have assessment of mood at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1" lower_limit="-4" upper_limit="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in mood score from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.17</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Muscle Function</title>
        <description>Assessment of muscle function using a hand dynamometer at weeks 0 and 8. Change in dominant handgrip strength in kilograms was calculated as 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did not have hand dynamometer data at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.&#xD;
Cholecalciferol: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Muscle Function</title>
          <description>Assessment of muscle function using a hand dynamometer at weeks 0 and 8. Change in dominant handgrip strength in kilograms was calculated as 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did not have hand dynamometer data at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>kilograms</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.2" lower_limit="-1.0" upper_limit="7.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in dominant handgrip strength from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.50</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Sleep Quality Assessment</title>
        <description>Assessment of sleep using the Pittsburgh Sleep Quality Index (PSQI) at weeks 0 and 8. Scores range from 0-21 with higher scores indicating poorer sleep quality. Change was calculated as week 8 minus week 0 PSQI. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did report the Pittsburgh Sleep Quality Index at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.&#xD;
Cholecalciferol: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Sleep Quality Assessment</title>
          <description>Assessment of sleep using the Pittsburgh Sleep Quality Index (PSQI) at weeks 0 and 8. Scores range from 0-21 with higher scores indicating poorer sleep quality. Change was calculated as week 8 minus week 0 PSQI. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did report the Pittsburgh Sleep Quality Index at week 8. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-1" lower_limit="-4" upper_limit="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in sleep quality assessment from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.16</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Functional Assessment of Cancer Therapy-breast</title>
        <description>Assessment of quality of life using the functional assessment of cancer therapy-breast symptoms at weeks 0 and 8. Scores range from 0-40 with higher scores indicating better quality of life.&#xD;
Change was calculated as week 8 score minus week 0 score. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did not have the Functional assessment of cancer therapy-breast at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.&#xD;
Cholecalciferol: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Functional Assessment of Cancer Therapy-breast</title>
          <description>Assessment of quality of life using the functional assessment of cancer therapy-breast symptoms at weeks 0 and 8. Scores range from 0-40 with higher scores indicating better quality of life.&#xD;
Change was calculated as week 8 score minus week 0 score. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did not have the Functional assessment of cancer therapy-breast at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="-7" upper_limit="17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in functional assessment of cancer therapy-breast score from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.75</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Functional Assessment of Cancer Therapy-endocrine</title>
        <description>Assessment of quality of life using the functional assessment of cancer therapy- endocrine symptoms at weeks 0 and 8. Scores range from 0-76 with higher scores indicating better quality of life. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
        <time_frame>0, 8 weeks</time_frame>
        <population>1 participant who initiated supplementation of cholecalciferol did not have the Functional assessment of cancer therapy-endocrine at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
        <group_list>
          <group group_id="O1">
            <title>Cholecalciferol</title>
            <description>All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.&#xD;
Cholecalciferol: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>No Cholecalciferol</title>
            <description>Enrolled women with serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Functional Assessment of Cancer Therapy-endocrine</title>
          <description>Assessment of quality of life using the functional assessment of cancer therapy- endocrine symptoms at weeks 0 and 8. Scores range from 0-76 with higher scores indicating better quality of life. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.</description>
          <population>1 participant who initiated supplementation of cholecalciferol did not have the Functional assessment of cancer therapy-endocrine at 8 weeks. Follow up laboratory and/or questionnaire data were not collected for women in the 'no cholecalciferol' arm.</population>
          <units>score on a scale</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9" lower_limit="-2" upper_limit="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>The null hypothesis is that there is 0 change in functional assessment of cancer therapy-endocrine score from week 0 to week 8.</groups_desc>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>0.19</p_value>
            <method>Wilcoxon signed rank test</method>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>8 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Intervention</title>
          <description>Enrolled women with serum 25 (OH)D less than 30 ng/ml received 50,000 IUs weekly supplementation of cholecalciferol for 8 weeks</description>
        </group>
        <group group_id="E2">
          <title>No Intervention</title>
          <description>Enrolled women without serum 25 (OH)D greater than or equal to 30 ng/ml received no intervention.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <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="3" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="3" subjects_affected="3" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="11"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="31"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Patricia Sheean</name_or_title>
      <organization>Loyola University Chicago</organization>
      <phone>708-216-0344</phone>
      <email>psheean1@luc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02186015
org study id: 206519
nct id: NCT02186015
lead sponsor: 
has dmc: No
Background: Several clinical trials are underway to investigate if variable forms of vitamin
      D (D2 vs. D3) prescribed at different doses (10,000-50,000 IUs/week) can improve the
      side-effects associated with treatment for estrogen receptor positive (ER+) breast cancer,
      specifically aromatase inhibitors (AIs.) Presumably for generalizability and potential safety
      purposes, these trials predominantly exclude women with metastatic breast cancer (MBC); a
      rapidly expanding sector of the cancer survivor population who experience significant
      treatment-related side-effects. Evaluation of the safety of vitamin D3 supplementation is
      crucial since supplementation can lead to high calcium and importantly, in lab studies have
      shown that vitamin D3 affects a gene that increases estrogen production. To assure that
      vitamin D3 does not affect the clinical effects of anti-estrogen therapies, the effect of
      vitamin D3 supplements on estrogen production requires an evaluation that further explores
      and defines its potential role in symptom management for this population.

      Objectives: This pilot study will evaluate the feasibility of vitamin D3 supplementation in
      women with MBC, providing much needed data on the preliminary safety and efficacy of this
      treatment in this patient population. This study will determine: 1) if weekly supplementation
      of high dose vitamin D3 increases serum vitamin D levels without adverse effects related to
      such therapy (primary aim); 2) the effects of vitamin D3 supplementation on symptom
      management (secondary aim); and 3) if vitamin D3 supplementation is associated with improved
      inflammation (exploratory aim.)

      Methods: This is an 8 week "proof of concept" study to monitor laboratory parameters and to
      assess potential effects on short-term outcomes. Adult, female patients (>=18 years) with ER+
      MBC (Stage IV) of any race/ethnicity and a history of vitamin D < 30 mg/dl will be recruited
      from within and around LUMC. Following current clinical practice guidelines, eligible
      participants will receive 50,000 IUs of vitamin D3 weekly for 8 weeks. Laboratory values,
      muscle function and inflammation will be examined pre- and post-supplementation, while
      symptoms will be assessed at baseline, 4 and 8 weeks post-supplementation. We will assess if
      increases in vitamin D are associated with clinically significant improvements in symptoms
      and QOL, and decreased inflammation.
Study Aims

      Several clinical trials are underway to investigate if vitamin D2 or D3 provided at various
      doses (10,000-50,000 IUs/week) can improve the side-effects associated with anti-estrogen
      therapies, specifically aromatase inhibitors (AIs). However, these current trials use
      variable forms of vitamin D and predominantly include women with Stage I-III disease,
      excluding women with metastatic breast cancer. Evaluation of the safety of vitamin D3
      supplementation is crucial since supplementation can lead to hypercalcemia and importantly,
      in vitro studies have shown that vitamin D3 influences the transcription of a gene that
      increases estrogen production.27,28 To assure that vitamin D3 does not abrogate the clinical
      effects of anti-estrogen therapies, the effect of vitamin D3 supplementation on estrogen
      production requires evaluation. Therefore, the overarching goal of this pilot study is to
      evaluate the safety, feasibility and efficacy of vitamin D3 supplementation in women with
      MBC. We will address and test the following aims and hypotheses, respectively:

      Aim 1: To determine if weekly supplementation of 50,000 IUs of vitamin D3 raises serum levels
      of 25(OH)D to >30 mg/dl without adverse effects.

      Hypothesis 1: Women who are compliant with vitamin D3 supplementation, as evidenced by
      normalization (>30 mg/dl) or increases in their serum 25(OH)D levels, will not experience
      significant changes in serum calcium, parathyroid hormone or serum estradiol levels.

      Aim 2: To determine the effect of vitamin D3 supplementation on symptom management.

      Hypothesis 2: Women who achieve serum concentrations of 25 (OH)D ≥30 mg/dl or experience
      significant increases in 25(OH)D will exhibit improvements in pain, fatigue, sleep, mood,
      muscle function and overall quality of life.

      Exploratory Aim: To explore the mechanistic effects of vitamin D3 supplementation on
      inflammatory markers and its potential association with symptom management.

      Summary: Evidence from studies involving early stage breast cancer participants confirms that
      musculoskeletal pain, endocrine related symptoms and mood disturbances are commonly
      associated with breast cancer treatment, particularly hormone deprivation therapies. The high
      prevalence of vitamin D deficiency/insufficiency among breast cancer survivors is well
      accepted and further hypothesized to aggravate treatment-related side effects, particularly
      arthralgias. Women with MBC are excluded from the majority of on-going vitamin D
      supplementation trials for safety and generalizability purposes. However, novel therapies are
      continuing to improve and prolong the lives of these women, resulting in a rapidly expansive
      group of breast cancer survivors. While vitamin D supplementation is prescribed to correct an
      underlying nutrient deficiency in the clinical context of preserving bone health, emerging
      evidence suggests it may have more systemic effects. Thus, vitamin D
      repletion/supplementation has profound potential implications for women with MBC, whose
      primary goal of treatment is to minimize the side-effects of treatment in support of optimal
      quality of life. This study reflects a highly innovative, yet simple therapy that could
      ultimately provide these survivors with a much needed evidence-based supportive care
      strategies.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Change in Serum 25(OH)D
time frame: 0, 8 weeks
description: Change in laboratory serum value of 25(OH)D at 8 weeks post-supplementation for participants who received weekly supplementation of 50,000 IUs of vitamin D3. Change is expressed as laboratory serum value of 25(OH)D at 8 weeks minus baseline. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
measure: Change in Worst Pain Rating From the Beck Pain Scale
time frame: 0, 8 weeks
description: Assessment of pain using the Beck Pain Scale at weeks 0 and 8. This is a Likert scale item where a score of 0 corresponds to no pain and a score of 10 corresponds to worst pain. Change is calculated as the worst pain rating at 8 weeks minus the worst pain rating at 0 weeks.Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
measure: Change in Fatigue
time frame: 0, 8 weeks
description: Assessment of fatigue using the Piper Fatigue Scale at weeks 0 and 8. The Piper Fatigue Scale is the average of 22 numeric items, with higher scores indicating greater fatigue [range of scores: 0-10]. Change is calculated as the fatigue score at 8 weeks minus fatigue score at 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
measure: Change in Mood
time frame: 0, 8 weeks
description: Assessment of mood using the Patient Health Questionnaire 8 (PHQ-8) at weeks 0 and 8. The PHQ-8 ranges from 0-24 with higher scores indicating more distress. Change was assessed as PHQ-8 score at 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
measure: Change in Muscle Function
time frame: 0, 8 weeks
description: Assessment of muscle function using a hand dynamometer at weeks 0 and 8. Change in dominant handgrip strength in kilograms was calculated as 8 weeks minus 0 weeks. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
measure: Change in Sleep Quality Assessment
time frame: 0, 8 weeks
description: Assessment of sleep using the Pittsburgh Sleep Quality Index (PSQI) at weeks 0 and 8. Scores range from 0-21 with higher scores indicating poorer sleep quality. Change was calculated as week 8 minus week 0 PSQI. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
measure: Change in Functional Assessment of Cancer Therapy-breast
time frame: 0, 8 weeks
description: Assessment of quality of life using the functional assessment of cancer therapy-breast symptoms at weeks 0 and 8. Scores range from 0-40 with higher scores indicating better quality of life.
Change was calculated as week 8 score minus week 0 score. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
measure: Change in Functional Assessment of Cancer Therapy-endocrine
time frame: 0, 8 weeks
description: Assessment of quality of life using the functional assessment of cancer therapy- endocrine symptoms at weeks 0 and 8. Scores range from 0-76 with higher scores indicating better quality of life. Change was not assessed for participants in the 'no cholecalciferol' arm since they did not receive weekly supplementation and were not followed over time.
arm group label: Cholecalciferol
arm group type: Experimental
description: All participants will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.
arm group label: Vitamin D sufficient
arm group type: No Intervention
description: All participants were ineligible for the intervention due to sufficient serum 25(OH)D levels at screening/baseline.
intervention type: Drug
intervention name: Cholecalciferol
description: Enrolled women will receive 50,000 IU weekly supplementation of cholecalciferol for 8 weeks.
arm group label: Cholecalciferol
other name: Vitamin D3
other name: Vitamin D
criteria: 
gender: Female
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Patricia M Sheean, Ph.D., R.D.
role: Principal Investigator
affiliation: Loyola University
facility: 
country: United States
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responsible party type: Principal Investigator
investigator affiliation: Loyola University
investigator full name: Patricia Sheean
investigator title: Research Associate
mesh term: Breast Neoplasms
mesh term: Vitamin D
mesh term: Ergocalciferols
mesh term: Cholecalciferol
mesh term: Vitamins
provided document: 
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participant flow: 
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outcome list: 
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point of contact: 