<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/NCT03003949</url>
  </required_header>
  <id_info>
    <org_study_id>16-1731</org_study_id>
    <secondary_id>1R01MH108690-01A1</secondary_id>
    <nct_id>NCT03003949</nct_id>
  </id_info>
  <brief_title>The Menopause Transition: Estrogen Variability, Stress Reactivity and Mood</brief_title>
  <acronym>Changes</acronym>
  <official_title>The Menopause Transition: Estrogen Variability, HPA Axis and Affective Symptoms</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of North Carolina, Chapel Hill</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Mental Health (NIMH)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of North Carolina, Chapel Hill</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Women in the menopause transition ('perimenopause') are exposed to extreme hormone&#xD;
      variability, tend to experience a unique set of severe stressors (e.g., divorce, death of&#xD;
      loved ones), and are also at substantially elevated risk to suffer from mood and anxiety&#xD;
      disorders. The purpose of this research is to understand the mechanisms by which variability&#xD;
      in estradiol (E2) is associated with the symptoms of anxiety and anhedonia (loss of interest&#xD;
      and pleasure - a common symptom of depression). By stabilizing E2 variability with a hormonal&#xD;
      manipulation, this research will determine the degree to which the E2 variability (or E2&#xD;
      levels) plays a causal role in perimenopausal anxiety and anhedonia symptoms and whether it&#xD;
      does so by affecting biological responses to stress.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Framed within a diathesis-stress model, the primary objective of this research is to&#xD;
      determine the pathophysiological mechanisms of estradiol (E2) in the clinical anxiety and&#xD;
      anhedonia seen in the menopause transition (MT). Specifically whether E2 variability or E2&#xD;
      levels predict exaggerated hypothalamic-pituitary-adrenal (HPA) axis reactivity and impaired&#xD;
      recovery to stress and, in turn, deficits in behavioral indices of threat responsivity and&#xD;
      approach motivation and symptoms of anxiety and anhedonia. The secondary objective of the&#xD;
      research is to use a hormonal manipulation as a mechanistic probe to stabilize E2 variability&#xD;
      in premenopausal ranges and determine if: a) HPA axis reactivity/recovery represents a&#xD;
      biomarker of behavioral and symptom responses to E2 stabilization; b) whether recent severe&#xD;
      life stress predicts the HPA axis response to hormone stabilization.&#xD;
&#xD;
      A total of 170 women in the early or late MT who are eligible for the hormonal probe will be&#xD;
      recruited to reflect the full continuum of anxiety and anhedonia symptoms based on&#xD;
      self-report to the State-Trait Anxiety Inventory and the Snaith-Hamilton Pleasure Scale,&#xD;
      respectively. However, the investigators will over-represent the clinically impairing end of&#xD;
      the anxious and anhedonic phenotype (75% of the sample). Over an 8-week baseline, anxiety and&#xD;
      anhedonia symptoms and serum E2 measured by liquid chromatography-tandem mass spectrometry&#xD;
      (LC-MS/MS) will be assessed on a weekly basis. At baseline week 8, HPA axis (plasma cortisol&#xD;
      and ACTH) response to the Trier Social Stress Test and behavioral measures of threat&#xD;
      responsivity (via Dot-Probe task) and approach motivation (Effort Expenditure for Rewards&#xD;
      Task 'EEfRT') will be determined. Using transdermal E2 as a pharmacological probe to&#xD;
      stabilize variability of E2 in premenopausal ranges, women will then be randomized to&#xD;
      transdermal E2 (0.10 mg) or placebo for 16 weeks. This is not a clinical efficacy trial. The&#xD;
      investigators will use an randomized control trial (RCT) design with a hormonal manipulation&#xD;
      in order to investigate the pathophysiologic role of E2 variability (or E2 levels) in HPA&#xD;
      axis dysregulation and, in turn, threat responsivity and approach motivation. Serum E2 will&#xD;
      be assessed weekly during weeks 9-16, and HPA axis reactivity to stress and behavioral&#xD;
      responses to the Dot-Probe and EEfRT tasks will be assessed every four weeks during the 16&#xD;
      week probe.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    In-person visit restrictions due to COVID-19&#xD;
  </why_stopped>
  <start_date type="Actual">January 24, 2017</start_date>
  <completion_date type="Actual">May 10, 2020</completion_date>
  <primary_completion_date type="Actual">May 10, 2020</primary_completion_date>
  <phase>Phase 4</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory</measure>
    <time_frame>Baseline (Week 8), Weeks 16, 20 and 24</time_frame>
    <description>The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Likert-type response scales (scores 0 - 3). The 20 questions are summed together for final score. The score can range from 0 to 60 with higher scores representing higher levels of anxiety. Change over time is defined as the difference in the least square means between timepoints and 95% confidence interval limits.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale</measure>
    <time_frame>Baseline (Week 8), Weeks 16, 20 and 24</time_frame>
    <description>Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. Change over time is defined as the difference in least square means between time points and 95% confidence interval limits.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change Over Time in AUC Cortisol Stress Response</measure>
    <time_frame>Baseline (Week 8), Weeks 16, 20 and 24</time_frame>
    <description>The stress biomarker cortisol (µg/dL) assessed at rest and in response to the Trier Social Stress test (AUC with respect to ground) at baseline (Week 8) and again post-randomization at weeks 16, 20 and 24. Blood serum samples for measuring cortisol are taken at immediately before the Trier Social Stress test and at 10, 20, 30, and 45 minutes post test. Change over time is defined as the difference in least square means between timepoints and with 95% confidence interval limits.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change Over Time in Threat Bias Score From Dot Probe Task</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>Changes in threat bias scores assessed using Dot Probe task during labs at weeks 8, 16, 20 and 24. The bias measurement protocol consists of 144 trials (48 threat congruent, 48 threat incongruent, 48 neutral presentations). Participants indicate the probe letter via button press. Angry face location, probe location, probe type and actor are all fully counterbalanced in presentation. The threat bias score equals the mean of reaction time on threat congruent from threat incongruent trials. A threat bias scores &gt;0 indicate a bias towards threat, whereas scores &lt;0 mean that the participant is slower to respond to threatening stimuli than neutral stimuli. Reaction times were measured in milliseconds. Change over time is defined as the difference in least square means between timepoints with 95% confidence interval limits.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change Over Time in Percent of &quot;Hard Task&quot; Choice in EEfRT</measure>
    <time_frame>up to 24 weeks</time_frame>
    <description>Effort Expenditure for Rewards Task (EEfRT) measures approach motivation that indexes the willingness to expend effort to obtain monetary rewards under varying conditions of reward probability and magnitude. On each trial, participants choose between an &quot;easy task&quot; and a &quot;hard task&quot; and are presented with information about the probability of winning (i.e., 12%, 50%, or 88%), and the magnitude of the potential reward if they complete the button-press task successfully (range: $1.24 - $4.12). Completion of the easy task requires 30 button presses in 7 seconds using the dominant index finger, whereas completion of the hard task requires 100 presses with the non-dominant &quot;pinky&quot; finger in 21 seconds. The percent of hard task choices is the dependent measure. Change over time is defined as the difference in least square means between time points with 95% confidence interval limits.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">82</enrollment>
  <condition>Perimenopausal Disorder</condition>
  <condition>Stress, Emotional</condition>
  <arm_group>
    <arm_group_label>Placebo Patch and Placebo Capsule</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Estradiol patch and progesterone capsule</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release</intervention_name>
    <description>Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).</description>
    <arm_group_label>Estradiol patch and progesterone capsule</arm_group_label>
    <other_name>Climara</other_name>
    <other_name>Prometrium</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Patch</intervention_name>
    <description>Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).</description>
    <arm_group_label>Placebo Patch and Placebo Capsule</arm_group_label>
    <other_name>Placebos</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Progesterone Capsule</intervention_name>
    <description>Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
    <arm_group_label>Estradiol patch and progesterone capsule</arm_group_label>
    <other_name>Progesterone</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Oral Capsule</intervention_name>
    <description>Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
    <arm_group_label>Placebo Patch and Placebo Capsule</arm_group_label>
    <other_name>Placebos</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Perimenopausal (either early perimenopause, defined as menstrual cycle length 7+ days&#xD;
             longer or shorter than usual; or the late perimenopause, defined as ≥2 skipped cycles&#xD;
             and an interval of amenorrhea ≥60 days but within one year of the last menstrual&#xD;
             period)&#xD;
&#xD;
          -  45 to 60 years of age&#xD;
&#xD;
          -  must be medically healthy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  a history of cardiovascular disease (CVD) including coronary artery disease,&#xD;
             arteriosclerosis, heart attack, or stroke&#xD;
&#xD;
          -  Type I or II diabetes&#xD;
&#xD;
          -  personal history of thrombotic events&#xD;
&#xD;
          -  personal or family history suggesting elevated risk for E2-related cancer&#xD;
&#xD;
          -  currently experiencing migraine headaches with aura&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>45 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Susan Girdler, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Research Professor</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>UNC SHARRP Lab</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27517</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Susan Girdler, PhD, Principal Investigator</name>
      <address>
        <city>Chapel Hill</city>
        <state>North Carolina</state>
        <zip>27599</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>December 6, 2016</study_first_submitted>
  <study_first_submitted_qc>December 21, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 28, 2016</study_first_posted>
  <results_first_submitted>March 2, 2021</results_first_submitted>
  <results_first_submitted_qc>March 2, 2021</results_first_submitted_qc>
  <results_first_posted type="Actual">March 26, 2021</results_first_posted>
  <last_update_submitted>March 2, 2021</last_update_submitted>
  <last_update_submitted_qc>March 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 26, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>perimenopause</keyword>
  <keyword>menopause transition</keyword>
  <keyword>estrogen</keyword>
  <keyword>stress</keyword>
  <keyword>mood</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Estradiol</mesh_term>
    <mesh_term>Progesterone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The investigators will submit data to the Research Domain Criteria Database (RDoCdb) and/or the National Database for Clinical Trials Related to Mental Illness (NDCT). The investigators will work with RDoCdb and NDCT staff to define data structures for any data being collected as part of the study. Descriptive data will be submitted two times per year and provide supporting documentation as necessary for others to more fully understand the manner in which data were collected. The investigators will submit cumulative data each submission cycle and will review data for any personally identifiable information and ensure that data are loaded correctly. The investigators will share data within 4 months after submission and submit experimental data within 12 months after study completion. Study data for each publication will be created and submit a link to the RDoCdb study along with any publications so readers of articles can link back to the data used in RDoCdb and NDCT.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>February 15, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/49/NCT03003949/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Placebo Patch and Placebo Capsule</title>
          <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
        </group>
        <group group_id="P2">
          <title>Estradiol Patch and Progesterone Capsule</title>
          <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Week 8</title>
              <participants_list>
                <participants group_id="P1" count="40"/>
                <participants group_id="P2" count="42"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Week 16</title>
              <participants_list>
                <participants group_id="P1" count="38"/>
                <participants group_id="P2" count="35"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Week 20</title>
              <participants_list>
                <participants group_id="P1" count="35"/>
                <participants group_id="P2" count="33"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Week 24</title>
              <participants_list>
                <participants group_id="P1" count="35"/>
                <participants group_id="P2" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="35"/>
                <participants group_id="P2" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="5"/>
                <participants group_id="P2" count="10"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Placebo Patch and Placebo Capsule</title>
          <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
        </group>
        <group group_id="B2">
          <title>Estradiol Patch and Progesterone Capsule</title>
          <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="40"/>
            <count group_id="B2" value="42"/>
            <count group_id="B3" value="82"/>
          </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="50.40" spread="2.52"/>
                    <measurement group_id="B2" value="49.39" spread="3.04"/>
                    <measurement group_id="B3" value="49.88" spread="2.83"/>
                  </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="40"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="82"/>
                  </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>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="37"/>
                    <measurement group_id="B2" value="39"/>
                    <measurement group_id="B3" value="76"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</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 (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="30"/>
                    <measurement group_id="B3" value="64"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</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>
                  <title>Unknown or Not Reported</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>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="82"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory</title>
        <description>The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Likert-type response scales (scores 0 - 3). The 20 questions are summed together for final score. The score can range from 0 to 60 with higher scores representing higher levels of anxiety. Change over time is defined as the difference in the least square means between timepoints and 95% confidence interval limits.</description>
        <time_frame>Baseline (Week 8), Weeks 16, 20 and 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo Patch and Placebo Capsule</title>
            <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol Patch and Progesterone Capsule</title>
            <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
          </group>
        </group_list>
        <measure>
          <title>Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory</title>
          <description>The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Likert-type response scales (scores 0 - 3). The 20 questions are summed together for final score. The score can range from 0 to 60 with higher scores representing higher levels of anxiety. Change over time is defined as the difference in the least square means between timepoints and 95% confidence interval limits.</description>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (Week 8) to Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2.74" lower_limit="-4.08" upper_limit="9.57"/>
                    <measurement group_id="O2" value="-0.89" lower_limit="-6.47" upper_limit="4.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 to Week 20</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-3.50" lower_limit="-10.56" upper_limit="3.56"/>
                    <measurement group_id="O2" value="0.19" lower_limit="-5.75" upper_limit="6.12"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 20 to Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3.63" lower_limit="-3.57" upper_limit="10.83"/>
                    <measurement group_id="O2" value="3.75" lower_limit="-2.24" upper_limit="9.73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale</title>
        <description>Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. Change over time is defined as the difference in least square means between time points and 95% confidence interval limits.</description>
        <time_frame>Baseline (Week 8), Weeks 16, 20 and 24</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Placebo Patch and Placebo Capsule</title>
            <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol Patch and Progesterone Capsule</title>
            <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
          </group>
        </group_list>
        <measure>
          <title>Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale</title>
          <description>Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. Change over time is defined as the difference in least square means between time points and 95% confidence interval limits.</description>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="40"/>
                <count group_id="O2" value="42"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (Week 8) to Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.01" lower_limit="-1.04" upper_limit="1.03"/>
                    <measurement group_id="O2" value="-0.63" lower_limit="-1.71" upper_limit="0.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 to Week 20</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.12" lower_limit="-0.87" upper_limit="1.27"/>
                    <measurement group_id="O2" value="0.88" lower_limit="-0.27" upper_limit="2.03"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 20 to Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.29" lower_limit="-0.79" upper_limit="1.38"/>
                    <measurement group_id="O2" value="-0.07" lower_limit="-1.22" upper_limit="1.08"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change Over Time in AUC Cortisol Stress Response</title>
        <description>The stress biomarker cortisol (µg/dL) assessed at rest and in response to the Trier Social Stress test (AUC with respect to ground) at baseline (Week 8) and again post-randomization at weeks 16, 20 and 24. Blood serum samples for measuring cortisol are taken at immediately before the Trier Social Stress test and at 10, 20, 30, and 45 minutes post test. Change over time is defined as the difference in least square means between timepoints and with 95% confidence interval limits.</description>
        <time_frame>Baseline (Week 8), Weeks 16, 20 and 24</time_frame>
        <population>Data reported for all samples collected.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo Patch and Placebo Capsule</title>
            <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol Patch and Progesterone Capsule</title>
            <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
          </group>
        </group_list>
        <measure>
          <title>Change Over Time in AUC Cortisol Stress Response</title>
          <description>The stress biomarker cortisol (µg/dL) assessed at rest and in response to the Trier Social Stress test (AUC with respect to ground) at baseline (Week 8) and again post-randomization at weeks 16, 20 and 24. Blood serum samples for measuring cortisol are taken at immediately before the Trier Social Stress test and at 10, 20, 30, and 45 minutes post test. Change over time is defined as the difference in least square means between timepoints and with 95% confidence interval limits.</description>
          <population>Data reported for all samples collected.</population>
          <units>µg/dL</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="33"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (Week 8) to Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.77" lower_limit="-160.13" upper_limit="229.67"/>
                    <measurement group_id="O2" value="245.50" lower_limit="-102.60" upper_limit="593.60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 to Week 20</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-7.30" lower_limit="-253.61" upper_limit="239.02"/>
                    <measurement group_id="O2" value="-244.20" lower_limit="-711.30" upper_limit="222.80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 20 to Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53.40" lower_limit="-239.71" upper_limit="346.51"/>
                    <measurement group_id="O2" value="88.80" lower_limit="-429.40" upper_limit="606.90"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change Over Time in Threat Bias Score From Dot Probe Task</title>
        <description>Changes in threat bias scores assessed using Dot Probe task during labs at weeks 8, 16, 20 and 24. The bias measurement protocol consists of 144 trials (48 threat congruent, 48 threat incongruent, 48 neutral presentations). Participants indicate the probe letter via button press. Angry face location, probe location, probe type and actor are all fully counterbalanced in presentation. The threat bias score equals the mean of reaction time on threat congruent from threat incongruent trials. A threat bias scores &gt;0 indicate a bias towards threat, whereas scores &lt;0 mean that the participant is slower to respond to threatening stimuli than neutral stimuli. Reaction times were measured in milliseconds. Change over time is defined as the difference in least square means between timepoints with 95% confidence interval limits.</description>
        <time_frame>up to 24 weeks</time_frame>
        <population>Data reported from tasks completed.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo Patch and Placebo Capsule</title>
            <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol Patch and Progesterone Capsule</title>
            <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
          </group>
        </group_list>
        <measure>
          <title>Change Over Time in Threat Bias Score From Dot Probe Task</title>
          <description>Changes in threat bias scores assessed using Dot Probe task during labs at weeks 8, 16, 20 and 24. The bias measurement protocol consists of 144 trials (48 threat congruent, 48 threat incongruent, 48 neutral presentations). Participants indicate the probe letter via button press. Angry face location, probe location, probe type and actor are all fully counterbalanced in presentation. The threat bias score equals the mean of reaction time on threat congruent from threat incongruent trials. A threat bias scores &gt;0 indicate a bias towards threat, whereas scores &lt;0 mean that the participant is slower to respond to threatening stimuli than neutral stimuli. Reaction times were measured in milliseconds. Change over time is defined as the difference in least square means between timepoints with 95% confidence interval limits.</description>
          <population>Data reported from tasks completed.</population>
          <units>milliseconds</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="41"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (Week 8) to Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-5.23" lower_limit="-21.51" upper_limit="11.06"/>
                    <measurement group_id="O2" value="-3.75" lower_limit="-14.95" upper_limit="7.45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 to Week 20</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-2.49" lower_limit="-19.75" upper_limit="14.78"/>
                    <measurement group_id="O2" value="-3.81" lower_limit="-15.79" upper_limit="8.16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 20 to Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.92" lower_limit="-18.31" upper_limit="16.47"/>
                    <measurement group_id="O2" value="7.25" lower_limit="-4.67" upper_limit="19.17"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change Over Time in Percent of &quot;Hard Task&quot; Choice in EEfRT</title>
        <description>Effort Expenditure for Rewards Task (EEfRT) measures approach motivation that indexes the willingness to expend effort to obtain monetary rewards under varying conditions of reward probability and magnitude. On each trial, participants choose between an &quot;easy task&quot; and a &quot;hard task&quot; and are presented with information about the probability of winning (i.e., 12%, 50%, or 88%), and the magnitude of the potential reward if they complete the button-press task successfully (range: $1.24 - $4.12). Completion of the easy task requires 30 button presses in 7 seconds using the dominant index finger, whereas completion of the hard task requires 100 presses with the non-dominant &quot;pinky&quot; finger in 21 seconds. The percent of hard task choices is the dependent measure. Change over time is defined as the difference in least square means between time points with 95% confidence interval limits.</description>
        <time_frame>up to 24 weeks</time_frame>
        <population>Data reported from tasks completed.</population>
        <group_list>
          <group group_id="O1">
            <title>Placebo Patch and Placebo Capsule</title>
            <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
          </group>
          <group group_id="O2">
            <title>Estradiol Patch and Progesterone Capsule</title>
            <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</description>
          </group>
        </group_list>
        <measure>
          <title>Change Over Time in Percent of &quot;Hard Task&quot; Choice in EEfRT</title>
          <description>Effort Expenditure for Rewards Task (EEfRT) measures approach motivation that indexes the willingness to expend effort to obtain monetary rewards under varying conditions of reward probability and magnitude. On each trial, participants choose between an &quot;easy task&quot; and a &quot;hard task&quot; and are presented with information about the probability of winning (i.e., 12%, 50%, or 88%), and the magnitude of the potential reward if they complete the button-press task successfully (range: $1.24 - $4.12). Completion of the easy task requires 30 button presses in 7 seconds using the dominant index finger, whereas completion of the hard task requires 100 presses with the non-dominant &quot;pinky&quot; finger in 21 seconds. The percent of hard task choices is the dependent measure. Change over time is defined as the difference in least square means between time points with 95% confidence interval limits.</description>
          <population>Data reported from tasks completed.</population>
          <units>percentage of &quot;hard task&quot; choices</units>
          <param>Least Squares Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="38"/>
                <count group_id="O2" value="36"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline (Week 8) to Week 16</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.0044" lower_limit="-0.1306" upper_limit="0.1219"/>
                    <measurement group_id="O2" value="0.0086" lower_limit="-0.0870" upper_limit="0.1042"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 16 to Week 20</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.0019" lower_limit="-0.1309" upper_limit="0.1347"/>
                    <measurement group_id="O2" value="0.0289" lower_limit="-0.0720" upper_limit="0.1298"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Week 20 to Week 24</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="-0.0045" lower_limit="-0.1392" upper_limit="0.1303"/>
                    <measurement group_id="O2" value="0.0200" lower_limit="-0.0885" upper_limit="0.1286"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From Baseline (Week 8) through study Week 24, an approximate total of 16 weeks.</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Placebo Patch and Placebo Capsule</title>
          <description>Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.&#xD;
Placebo Patch: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).&#xD;
Placebo Oral Capsule: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.</description>
        </group>
        <group group_id="E2">
          <title>Estradiol Patch and Progesterone Capsule</title>
          <description>Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.&#xD;
Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).&#xD;
Progesterone Capsule: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week</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="40"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="42"/>
              </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="39" subjects_at_risk="40"/>
                <counts group_id="E2" subjects_affected="39" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="40"/>
                <counts group_id="E2" events="10" subjects_affected="8" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="14" subjects_affected="12" subjects_at_risk="40"/>
                <counts group_id="E2" events="24" subjects_affected="15" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Lightheadedness</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="40"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="40"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Musculoskeletal pain</sub_title>
                <counts group_id="E1" events="29" subjects_affected="17" subjects_at_risk="40"/>
                <counts group_id="E2" events="20" subjects_affected="12" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache (Non-Migraine)</sub_title>
                <counts group_id="E1" events="75" subjects_affected="29" subjects_at_risk="40"/>
                <counts group_id="E2" events="63" subjects_affected="27" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Migraine</sub_title>
                <counts group_id="E1" events="8" subjects_affected="5" subjects_at_risk="40"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Negative Mood Change</sub_title>
                <counts group_id="E1" events="37" subjects_affected="17" subjects_at_risk="40"/>
                <counts group_id="E2" events="27" subjects_affected="17" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Breast tenderness</sub_title>
                <counts group_id="E1" events="16" subjects_affected="11" subjects_at_risk="40"/>
                <counts group_id="E2" events="91" subjects_affected="30" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Profuse menstrual bleeding</sub_title>
                <description>Profuse is defined as &gt;3 tampons or pads for &gt; 5 days or &gt; 1 tampon or pad per hour on any given day.</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="40"/>
                <counts group_id="E2" events="13" subjects_affected="10" subjects_at_risk="42"/>
              </event>
              <event>
                <sub_title>Prolonged menstrual bleeding</sub_title>
                <description>Menstrual bleeding &gt; 10 days.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="40"/>
                <counts group_id="E2" events="5" subjects_affected="5" subjects_at_risk="42"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Skin irritation (at patch site)</sub_title>
                <counts group_id="E1" events="36" subjects_affected="18" subjects_at_risk="40"/>
                <counts group_id="E2" events="96" subjects_affected="33" subjects_at_risk="42"/>
              </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>Susan Girdler, PhD</name_or_title>
      <organization>University of North Carolina at Chapel Hill</organization>
      <phone>919-590-0813</phone>
      <email>rachel_kozik@med.unc.edu</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03003949
org study id: 16-1731
secondary id: 1R01MH108690-01A1
nct id: NCT03003949
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Women in the menopause transition ('perimenopause') are exposed to extreme hormone
      variability, tend to experience a unique set of severe stressors (e.g., divorce, death of
      loved ones), and are also at substantially elevated risk to suffer from mood and anxiety
      disorders. The purpose of this research is to understand the mechanisms by which variability
      in estradiol (E2) is associated with the symptoms of anxiety and anhedonia (loss of interest
      and pleasure - a common symptom of depression). By stabilizing E2 variability with a hormonal
      manipulation, this research will determine the degree to which the E2 variability (or E2
      levels) plays a causal role in perimenopausal anxiety and anhedonia symptoms and whether it
      does so by affecting biological responses to stress.
Framed within a diathesis-stress model, the primary objective of this research is to
      determine the pathophysiological mechanisms of estradiol (E2) in the clinical anxiety and
      anhedonia seen in the menopause transition (MT). Specifically whether E2 variability or E2
      levels predict exaggerated hypothalamic-pituitary-adrenal (HPA) axis reactivity and impaired
      recovery to stress and, in turn, deficits in behavioral indices of threat responsivity and
      approach motivation and symptoms of anxiety and anhedonia. The secondary objective of the
      research is to use a hormonal manipulation as a mechanistic probe to stabilize E2 variability
      in premenopausal ranges and determine if: a) HPA axis reactivity/recovery represents a
      biomarker of behavioral and symptom responses to E2 stabilization; b) whether recent severe
      life stress predicts the HPA axis response to hormone stabilization.

      A total of 170 women in the early or late MT who are eligible for the hormonal probe will be
      recruited to reflect the full continuum of anxiety and anhedonia symptoms based on
      self-report to the State-Trait Anxiety Inventory and the Snaith-Hamilton Pleasure Scale,
      respectively. However, the investigators will over-represent the clinically impairing end of
      the anxious and anhedonic phenotype (75% of the sample). Over an 8-week baseline, anxiety and
      anhedonia symptoms and serum E2 measured by liquid chromatography-tandem mass spectrometry
      (LC-MS/MS) will be assessed on a weekly basis. At baseline week 8, HPA axis (plasma cortisol
      and ACTH) response to the Trier Social Stress Test and behavioral measures of threat
      responsivity (via Dot-Probe task) and approach motivation (Effort Expenditure for Rewards
      Task 'EEfRT') will be determined. Using transdermal E2 as a pharmacological probe to
      stabilize variability of E2 in premenopausal ranges, women will then be randomized to
      transdermal E2 (0.10 mg) or placebo for 16 weeks. This is not a clinical efficacy trial. The
      investigators will use an randomized control trial (RCT) design with a hormonal manipulation
      in order to investigate the pathophysiologic role of E2 variability (or E2 levels) in HPA
      axis dysregulation and, in turn, threat responsivity and approach motivation. Serum E2 will
      be assessed weekly during weeks 9-16, and HPA axis reactivity to stress and behavioral
      responses to the Dot-Probe and EEfRT tasks will be assessed every four weeks during the 16
      week probe.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Double (Participant, Investigator)
measure: Change Over Time in the Anxiety Score From State-Trait Anxiety Inventory
time frame: Baseline (Week 8), Weeks 16, 20 and 24
description: The State-Trait anxiety inventory is consists of 20 questions on a 4-point force-choice Likert-type response scales (scores 0 - 3). The 20 questions are summed together for final score. The score can range from 0 to 60 with higher scores representing higher levels of anxiety. Change over time is defined as the difference in the least square means between timepoints and 95% confidence interval limits.
measure: Change Over Time in Anhedonia Score From Snaith-Hamilton Pleasure Scale
time frame: Baseline (Week 8), Weeks 16, 20 and 24
description: Anhedonia will be assessed using SHAPS scores which range from 14-56, with higher scores corresponding to higher levels of anhedonia. Change over time is defined as the difference in least square means between time points and 95% confidence interval limits.
measure: Change Over Time in AUC Cortisol Stress Response
time frame: Baseline (Week 8), Weeks 16, 20 and 24
description: The stress biomarker cortisol (µg/dL) assessed at rest and in response to the Trier Social Stress test (AUC with respect to ground) at baseline (Week 8) and again post-randomization at weeks 16, 20 and 24. Blood serum samples for measuring cortisol are taken at immediately before the Trier Social Stress test and at 10, 20, 30, and 45 minutes post test. Change over time is defined as the difference in least square means between timepoints and with 95% confidence interval limits.
measure: Change Over Time in Threat Bias Score From Dot Probe Task
time frame: up to 24 weeks
description: Changes in threat bias scores assessed using Dot Probe task during labs at weeks 8, 16, 20 and 24. The bias measurement protocol consists of 144 trials (48 threat congruent, 48 threat incongruent, 48 neutral presentations). Participants indicate the probe letter via button press. Angry face location, probe location, probe type and actor are all fully counterbalanced in presentation. The threat bias score equals the mean of reaction time on threat congruent from threat incongruent trials. A threat bias scores >0 indicate a bias towards threat, whereas scores <0 mean that the participant is slower to respond to threatening stimuli than neutral stimuli. Reaction times were measured in milliseconds. Change over time is defined as the difference in least square means between timepoints with 95% confidence interval limits.
measure: Change Over Time in Percent of "Hard Task" Choice in EEfRT
time frame: up to 24 weeks
description: Effort Expenditure for Rewards Task (EEfRT) measures approach motivation that indexes the willingness to expend effort to obtain monetary rewards under varying conditions of reward probability and magnitude. On each trial, participants choose between an "easy task" and a "hard task" and are presented with information about the probability of winning (i.e., 12%, 50%, or 88%), and the magnitude of the potential reward if they complete the button-press task successfully (range: $1.24 - $4.12). Completion of the easy task requires 30 button presses in 7 seconds using the dominant index finger, whereas completion of the hard task requires 100 presses with the non-dominant "pinky" finger in 21 seconds. The percent of hard task choices is the dependent measure. Change over time is defined as the difference in least square means between time points with 95% confidence interval limits.
arm group label: Placebo Patch and Placebo Capsule
arm group type: Placebo Comparator
description: Placebo patches worn for 16 weeks. On the 9th week of patch, oral placebo capsule taken daily for 12 days. Following the 16 weeks of patch use oral placebo capsule taken daily for 12 days.
arm group label: Estradiol patch and progesterone capsule
arm group type: Active Comparator
description: Estradiol patches worn for 16 weeks. On the 9th week of patch, oral progesterone capsule taken daily for 12 days. Following the 16 weeks of estradiol patch use oral progesterone capsule taken daily for 12 days.
intervention type: Drug
intervention name: Estradiol Patch, 0.1 Mg/24 Hours Weekly Transdermal Film, Extended Release
description: Transdermal Estradiol worn daily for 16 weeks (patch changed every 7 days).
arm group label: Estradiol patch and progesterone capsule
other name: Climara
other name: Prometrium
intervention type: Drug
intervention name: Placebo Patch
description: Matching placebo patches to be worn every day for 16 weeks (patch changed every 7 days).
arm group label: Placebo Patch and Placebo Capsule
other name: Placebos
intervention type: Drug
intervention name: Progesterone Capsule
description: Micronized progesterone (200 mg) will be administered every day for 12 days during the 9th week of randomization and again following randomization at the 17th week
arm group label: Estradiol patch and progesterone capsule
other name: Progesterone
intervention type: Drug
intervention name: Placebo Oral Capsule
description: Matching placebo capsules will be administered orally every day for 12 days during the 9th week of randomization and again following randomization at the 17th week.
arm group label: Placebo Patch and Placebo Capsule
other name: Placebos
criteria: 
gender: Female
minimum age: 45 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Susan Girdler, PhD
role: Principal Investigator
affiliation: Research Professor
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Estradiol
mesh term: Progesterone
sharing ipd: Yes
ipd description: The investigators will submit data to the Research Domain Criteria Database (RDoCdb) and/or the National Database for Clinical Trials Related to Mental Illness (NDCT). The investigators will work with RDoCdb and NDCT staff to define data structures for any data being collected as part of the study. Descriptive data will be submitted two times per year and provide supporting documentation as necessary for others to more fully understand the manner in which data were collected. The investigators will submit cumulative data each submission cycle and will review data for any personally identifiable information and ensure that data are loaded correctly. The investigators will share data within 4 months after submission and submit experimental data within 12 months after study completion. Study data for each publication will be created and submit a link to the RDoCdb study along with any publications so readers of articles can link back to the data used in RDoCdb and NDCT.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 