<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/NCT03018366</url>
  </required_header>
  <id_info>
    <org_study_id>PRO26081</org_study_id>
    <nct_id>NCT03018366</nct_id>
  </id_info>
  <brief_title>Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women</brief_title>
  <official_title>Atherosclerosis, Immune Mediated Inflammation and Hypoestrogenemia in Young Women</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cedars-Sinai Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cedars-Sinai Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine whether low estrogen levels in young women with&#xD;
      hypothalamic amenorrhea (premenopausal HypoE) is associated with risk factors for&#xD;
      cardiovascular disease.&#xD;
&#xD;
      For this study, the investigators will measuring vascular function and immune markers on:&#xD;
&#xD;
        -  young women with hypothalamic amenorrhea (&gt;3 months of no menstrual cycle due to low&#xD;
           estrogen)&#xD;
&#xD;
        -  young women with regular menstrual cycles not on hormone therapy.&#xD;
&#xD;
        -  recently menopausal women (&lt;3 years from final menstrual period) not on hormone therapy.&#xD;
&#xD;
      Premenopausal HypoE participants will then be randomized to use either an estrogen patch or a&#xD;
      placebo patch (no active medicine) for 3 months, followed by estrogen or placebo patch plus&#xD;
      progesterone or placebo pills for 2 additional weeks. The investigators are looking to see if&#xD;
      estrogen improves vascular and immune function.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Aims:&#xD;
&#xD;
        1. To test the hypothesis premenopausal HypoE is associated with pre-clinical CVD as&#xD;
           determined by reductions in vascular endothelial function and increased central arterial&#xD;
           stiffness.&#xD;
&#xD;
        2. To test the hypothesis premenopausal HypoE is associated with increased immune-mediated&#xD;
           inflammation.&#xD;
&#xD;
        3. To test the hypothesis estrogens can reduce inflammation, improve vascular endothelial&#xD;
           function and central arterial stiffness in premenopausal HypoE women.&#xD;
&#xD;
      In a randomized, double-blind placebo-controlled trial in premenopausal HypoE women the&#xD;
      investigators will test 12 weeks of transdermal estradiol 0.1 mg/day patch or placebo&#xD;
      followed by 2 weeks of estradiol plus progesterone 200mg on vascular endothelial function,&#xD;
      arterial stiffness and immune-mediated inflammation versus placebo. Patches will be applied&#xD;
      by the participant to the lower abdomen twice weekly, alternating sides.&#xD;
&#xD;
      The investigators will be using non-invasive tests to measure vascular function including:&#xD;
&#xD;
        -  Peripheral arterial tonometry (PAT)&#xD;
&#xD;
        -  SphygmoCor measurements of central blood pressure&#xD;
&#xD;
        -  Carotid intima-media thickness (CIMT)&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 1, 2017</start_date>
  <completion_date type="Actual">February 1, 2023</completion_date>
  <primary_completion_date type="Actual">February 1, 2023</primary_completion_date>
  <phase>Phase 2</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>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Rate of change of peripheral arterial tonometry (PAT)</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>PAT measured as reactive hyperemia index (RHI%)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Rate of change of pulse wave analysis</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>SphymoCor measured as augmentation index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Rate of change of pulse wave velocity</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>SphymoCor measured as meters/second</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Serum Inflammatory Markers</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hormone levels</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life (questionnaire)</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>Short-Form Health Survey 12</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Depression</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>Patient Health Questionnaire (PHQ-9)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Sleep changes</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>Insomnia Severity Index</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Anxiety</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>Overall Anxiety Severity and Impairment Scale (OASIS)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Stress</measure>
    <time_frame>Baseline, week 6, 12, and 14 on trial</time_frame>
    <description>Cohen Perceived Stress Scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>DEXA Scan</measure>
    <time_frame>Baseline</time_frame>
    <description>dual-energy x-ray absorptiometry (DEXA) bone mass</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">29</enrollment>
  <condition>Estrogen Deficiency</condition>
  <condition>Cardiovascular Disease (CVD)</condition>
  <condition>Hypothalamic Amenorrhea</condition>
  <arm_group>
    <arm_group_label>17Beta Estradiol, Progesterone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>17Beta Estradiol (0.1mg/day) , Progesterone (100mg) or Medroxyprogesterone (10mg) for patient with a peanut allergy because progesterone 100mg is a peanut based product</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Transdermal Placebo Patch, Placebo Pill</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo Transdermal Patch, Placebo Pill</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>17beta Estradiol</intervention_name>
    <description>Participants will use a dose of transdermal estradiol 0.1 mg/day patch for 12 weeks +/- 1week. PAT index vascular measures and serum immune markers will be measured after 6 and 12 weeks +/- 1week on estrogen patches. Patches will be applied by the participant to the lower abdomen twice weekly, alternating sides.</description>
    <arm_group_label>17Beta Estradiol, Progesterone</arm_group_label>
    <other_name>Estradiol Transdermal Patch</other_name>
    <other_name>Vivelle-Dot</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Transdermal placebo patch</intervention_name>
    <description>Participants will use a dose of placebo patches for 12 weeks +/- 1 week. Placebos will be applied by the participant to the lower abdomen twice weekly, alternating sides.</description>
    <arm_group_label>Transdermal Placebo Patch, Placebo Pill</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Progesterone</intervention_name>
    <description>After 12 weeks +/- 1week of transdermal estradiol patch, participants will use estrogen patch plus progesterone for 2 additional weeks +/- 3 days. Progesterone is a peanut based product and for patients with a peanut allergy we will replace this with a synthetic progestin at an equivalent dose, medroxyprogesterone 10mg.</description>
    <arm_group_label>17Beta Estradiol, Progesterone</arm_group_label>
    <other_name>Prometrium</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo Pill</intervention_name>
    <description>After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days.</description>
    <arm_group_label>Transdermal Placebo Patch, Placebo Pill</arm_group_label>
    <other_name>Placebo Oral Pill</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        For premenopausal Hypo E and normal control women, inclusions include:&#xD;
&#xD;
          -  Premenopausal currently not on hormone therapy,&#xD;
&#xD;
          -  English speaking (for the purposes of complete psychosocial assessment)&#xD;
&#xD;
          -  able to give informed consent&#xD;
&#xD;
          -  a gynecological age (age since menarche) &gt; 10 and &lt; 25 years, and chronological age &gt;&#xD;
             18 years&#xD;
&#xD;
          -  Within 90-110% of ideal body weight as determined by the 1983 Metropolitan Height and&#xD;
             weight table for women&#xD;
&#xD;
          -  All participants with hypothalamic amenorrhea will be diagnosed based on exclusion of&#xD;
             other etiologies for their amenorrhea, including pregnancy, thyroid dysfunction,&#xD;
             hyperprolactinemia, premature ovarian insufficiency, and polycystic ovary disease&#xD;
&#xD;
        For recently menopausal women inclusions include:&#xD;
&#xD;
          -  Follicle stimulating hormones (FSH) &gt;30 and 12 months of amenorrhea, within 3 years of&#xD;
             final menstrual period with natural menopausal not on hormone therapy&#xD;
&#xD;
          -  English speaking&#xD;
&#xD;
          -  Able to give informed consent&#xD;
&#xD;
          -  Within 90-110% of ideal body weight&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        For premenopausal Hypo E and normal control women exclusions include:&#xD;
&#xD;
          -  Smoking&#xD;
&#xD;
          -  Hypertension&#xD;
&#xD;
          -  Hyperlipidemia&#xD;
&#xD;
          -  Diabetes&#xD;
&#xD;
          -  Medications including psychotropic or illicit drugs, medical, neurological&#xD;
&#xD;
          -  Ophthalmologic disease except acuity problems&#xD;
&#xD;
          -  Major Axis I disorder other than depression&#xD;
&#xD;
          -  Pregnancy in the last 12 months and/or lactating in the last 6 months&#xD;
&#xD;
          -  Current use of hormone contraceptive or any estrogen or progestin therapy&#xD;
&#xD;
        For HypoE women, exclusion criteria include:&#xD;
&#xD;
        - Allergy to adhesive or tape&#xD;
&#xD;
        For recently menopausal women exclusions also include:&#xD;
&#xD;
          -  Previous or current use of hormone therapy, estrogen or progestin&#xD;
&#xD;
          -  Surgical or chemotherapy induced menopause&#xD;
&#xD;
          -  Premature ovarian failure&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Chrisandra Shufelt, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Noel Bairey-Merz, MD</last_name>
    <role>Study Director</role>
    <affiliation>Cedars-Sinai Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cedars-Sinai Barbra Streisand Women's Heart Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90048</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>December 1, 2016</study_first_submitted>
  <study_first_submitted_qc>January 10, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 12, 2017</study_first_posted>
  <last_update_submitted>May 11, 2023</last_update_submitted>
  <last_update_submitted_qc>May 11, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 15, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mayo Clinic</investigator_affiliation>
    <investigator_full_name>Chrisandra Shufelt</investigator_full_name>
    <investigator_title>Professor and Chair, Division of General Internal Medicine</investigator_title>
  </responsible_party>
  <keyword>estrogen</keyword>
  <keyword>premenopause</keyword>
  <keyword>menopause</keyword>
  <keyword>amenorrhea</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cardiovascular Diseases</mesh_term>
    <mesh_term>Atherosclerosis</mesh_term>
    <mesh_term>Inflammation</mesh_term>
    <mesh_term>Amenorrhea</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Estradiol 17 beta-cypionate</mesh_term>
    <mesh_term>Estradiol 3-benzoate</mesh_term>
    <mesh_term>Estradiol</mesh_term>
    <mesh_term>Polyestradiol phosphate</mesh_term>
    <mesh_term>Progesterone</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</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/NCT03018366
org study id: PRO26081
nct id: NCT03018366
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The purpose of this study is to determine whether low estrogen levels in young women with
      hypothalamic amenorrhea (premenopausal HypoE) is associated with risk factors for
      cardiovascular disease.

      For this study, the investigators will measuring vascular function and immune markers on:

        -  young women with hypothalamic amenorrhea (>3 months of no menstrual cycle due to low
           estrogen)

        -  young women with regular menstrual cycles not on hormone therapy.

        -  recently menopausal women (<3 years from final menstrual period) not on hormone therapy.

      Premenopausal HypoE participants will then be randomized to use either an estrogen patch or a
      placebo patch (no active medicine) for 3 months, followed by estrogen or placebo patch plus
      progesterone or placebo pills for 2 additional weeks. The investigators are looking to see if
      estrogen improves vascular and immune function.
Study Aims:

        1. To test the hypothesis premenopausal HypoE is associated with pre-clinical CVD as
           determined by reductions in vascular endothelial function and increased central arterial
           stiffness.

        2. To test the hypothesis premenopausal HypoE is associated with increased immune-mediated
           inflammation.

        3. To test the hypothesis estrogens can reduce inflammation, improve vascular endothelial
           function and central arterial stiffness in premenopausal HypoE women.

      In a randomized, double-blind placebo-controlled trial in premenopausal HypoE women the
      investigators will test 12 weeks of transdermal estradiol 0.1 mg/day patch or placebo
      followed by 2 weeks of estradiol plus progesterone 200mg on vascular endothelial function,
      arterial stiffness and immune-mediated inflammation versus placebo. Patches will be applied
      by the participant to the lower abdomen twice weekly, alternating sides.

      The investigators will be using non-invasive tests to measure vascular function including:

        -  Peripheral arterial tonometry (PAT)

        -  SphygmoCor measurements of central blood pressure

        -  Carotid intima-media thickness (CIMT)
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Rate of change of peripheral arterial tonometry (PAT)
time frame: Baseline, week 6, 12, and 14 on trial
description: PAT measured as reactive hyperemia index (RHI%)
measure: Rate of change of pulse wave analysis
time frame: Baseline, week 6, 12, and 14 on trial
description: SphymoCor measured as augmentation index
measure: Rate of change of pulse wave velocity
time frame: Baseline, week 6, 12, and 14 on trial
description: SphymoCor measured as meters/second
measure: Serum Inflammatory Markers
time frame: Baseline, week 6, 12, and 14 on trial
measure: Hormone levels
time frame: Baseline, week 6, 12, and 14 on trial
measure: Quality of life (questionnaire)
time frame: Baseline, week 6, 12, and 14 on trial
description: Short-Form Health Survey 12
measure: Depression
time frame: Baseline, week 6, 12, and 14 on trial
description: Patient Health Questionnaire (PHQ-9)
measure: Sleep changes
time frame: Baseline, week 6, 12, and 14 on trial
description: Insomnia Severity Index
measure: Anxiety
time frame: Baseline, week 6, 12, and 14 on trial
description: Overall Anxiety Severity and Impairment Scale (OASIS)
measure: Stress
time frame: Baseline, week 6, 12, and 14 on trial
description: Cohen Perceived Stress Scale
measure: DEXA Scan
time frame: Baseline
description: dual-energy x-ray absorptiometry (DEXA) bone mass
arm group label: 17Beta Estradiol, Progesterone
arm group type: Active Comparator
description: 17Beta Estradiol (0.1mg/day) , Progesterone (100mg) or Medroxyprogesterone (10mg) for patient with a peanut allergy because progesterone 100mg is a peanut based product
arm group label: Transdermal Placebo Patch, Placebo Pill
arm group type: Placebo Comparator
description: Placebo Transdermal Patch, Placebo Pill
intervention type: Drug
intervention name: 17beta Estradiol
description: Participants will use a dose of transdermal estradiol 0.1 mg/day patch for 12 weeks +/- 1week. PAT index vascular measures and serum immune markers will be measured after 6 and 12 weeks +/- 1week on estrogen patches. Patches will be applied by the participant to the lower abdomen twice weekly, alternating sides.
arm group label: 17Beta Estradiol, Progesterone
other name: Estradiol Transdermal Patch
other name: Vivelle-Dot
intervention type: Drug
intervention name: Transdermal placebo patch
description: Participants will use a dose of placebo patches for 12 weeks +/- 1 week. Placebos will be applied by the participant to the lower abdomen twice weekly, alternating sides.
arm group label: Transdermal Placebo Patch, Placebo Pill
intervention type: Drug
intervention name: Progesterone
description: After 12 weeks +/- 1week of transdermal estradiol patch, participants will use estrogen patch plus progesterone for 2 additional weeks +/- 3 days. Progesterone is a peanut based product and for patients with a peanut allergy we will replace this with a synthetic progestin at an equivalent dose, medroxyprogesterone 10mg.
arm group label: 17Beta Estradiol, Progesterone
other name: Prometrium
intervention type: Drug
intervention name: Placebo Pill
description: After 12 weeks +/- 1week of transdermal placebo patch, participants will use placebo patch plus placebo pill for 2 additional weeks +/- 3 days.
arm group label: Transdermal Placebo Patch, Placebo Pill
other name: Placebo Oral Pill
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Chrisandra Shufelt, MD
role: Principal Investigator
affiliation: Cedars-Sinai Medical Center
last name: Noel Bairey-Merz, MD
role: Study Director
affiliation: Cedars-Sinai Medical Center
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Mayo Clinic
investigator full name: Chrisandra Shufelt
investigator title: Professor and Chair, Division of General Internal Medicine
mesh term: Cardiovascular Diseases
mesh term: Atherosclerosis
mesh term: Inflammation
mesh term: Amenorrhea
mesh term: Estradiol 17 beta-cypionate
mesh term: Estradiol 3-benzoate
mesh term: Estradiol
mesh term: Polyestradiol phosphate
mesh term: Progesterone
sharing ipd: No