<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/NCT03825120</url>
  </required_header>
  <id_info>
    <org_study_id>R01AG053332</org_study_id>
    <secondary_id>1R01AG053332-01A1</secondary_id>
    <nct_id>NCT03825120</nct_id>
  </id_info>
  <brief_title>The Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk</brief_title>
  <acronym>OVACV</acronym>
  <official_title>The Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of California, San Francisco</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of California, San Francisco</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Despite significant improvements in prevention and treatment of cardiovascular disease (CVD),&#xD;
      the growing aging population suggests CVD will continue to pose a significant public health&#xD;
      burden. Women are a special group where microvascular disease is more common and traditional&#xD;
      risk factors may not fully identify risk. Women's reproductive history (e.g. menarcheal age,&#xD;
      menstrual cycles, infertility, pregnancy, menopause) may pose unique risk and suggests an&#xD;
      opportunity for new approaches. The investigators propose a women-centered approach for early&#xD;
      identification of women at risk that investigates the unique loss of reproductive function at&#xD;
      an age long before other vital systems fail. Despite its importance, little is known about&#xD;
      the determinants or correlates of ovarian aging, or the health implications, especially in&#xD;
      diverse communities. Only recently have reliable biomarkers of the remaining oocyte pool been&#xD;
      available for use in normally cycling women. This availability gives us a unique opportunity&#xD;
      to characterize the association between &quot;ovarian age&quot; (cross-sectional) and the rate of&#xD;
      &quot;ovarian aging&quot; or oocyte decline over time (longitudinal) and the health implications of&#xD;
      accelerated oocyte loss. The investigators hypothesize ovarian age/aging provides a window&#xD;
      onto the general health of women. The investigators suggest it is not the progressive&#xD;
      deficiency of estrogen with menopause that increases risk, but common underlying cellular&#xD;
      aging mechanisms first evident in young populations as lower ovarian reserve (follicle&#xD;
      number) due to the unique sensitivity of the ovary.&#xD;
&#xD;
      Studies of cellular aging focused on mitochondrial dysfunction, oxidative stress,&#xD;
      inflammation, and telomere length have identified correlations with CVD risk. Improved&#xD;
      understanding of the mechanisms of cellular aging suggests telomere shortening and&#xD;
      dysfunction may drive mitochondrial dysfunction and potentially the parallel between cellular&#xD;
      aging and CVD. The oocyte is particularly sensitive to mitochondrial dysfunction, having 10&#xD;
      times the number of mitochondria as any somatic cell. Additionally, mitochondrial dysfunction&#xD;
      and telomere shortening have been associated with ovarian aging. This begs the question of&#xD;
      whether, given the susceptibility of the ovary to mitochondrial dysfunction, accelerated&#xD;
      ovarian aging may be a harbinger of subsequent CVD risk. To address this critical question,&#xD;
      the investigators propose to leverage the largest and most ethnically diverse population of&#xD;
      normal reproductive-aged women, with detailed measures of ovarian age, and to deploy&#xD;
      peripheral endothelial function testing, a non-invasive sensitive marker of early CVD risk.&#xD;
      Ovarian aging is thought to be largely genetically determined, but the impact of&#xD;
      race/ethnicity has not been fully explored. Evaluating the impact of ethnicity on ovarian&#xD;
      aging, and combining this information with the impact of modifiable behavioral risk factors,&#xD;
      may help clarify CVD risk in young, ethnically-diverse, reproductive-age women. The&#xD;
      investigators believe improving our understanding of factors that affect the rate of&#xD;
      oocyte/follicle loss and the relationship with CVD risk factors will promote a novel method&#xD;
      to identify women at earlier and/or increased cardiac risk.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigators propose to carry out three Specific Aims:&#xD;
&#xD;
        1. Determine whether markers of ovarian age/aging are associated with increased CVD risk.&#xD;
&#xD;
           Specifically, the investigators propose to assess whether:&#xD;
&#xD;
             1. Ovarian age predicts CVD risk (measured by peripheral endothelial function testing)&#xD;
                independent of chronological age.&#xD;
&#xD;
             2. The rate of ovarian aging is independently associated with increased CVD risk after&#xD;
                adjustment for ovarian and chronological age.&#xD;
&#xD;
        2. Determine whether ovarian aging may moderate or mediate established associations between&#xD;
           race/ethnicity and CVD risk and socio/emotional health and CVD risk. Specifically, the&#xD;
           investigators propose to:&#xD;
&#xD;
             1. Examine whether observed race/ethnic disparities in CVD risk (measured by&#xD;
                peripheral endothelial function testing) may vary by (moderation model) or be&#xD;
                partially attributable to (mediation model) ovarian aging.&#xD;
&#xD;
             2. Examine whether effects of socio/emotional health (as indexed by separate&#xD;
                composites of psychosocial functioning and socioeconomic status) on CVD risk may&#xD;
                vary by (moderation model) or be partially attributable to (mediation model)&#xD;
                ovarian aging.&#xD;
&#xD;
        3. Determine if similar mechanisms of cellular aging underlie both ovarian aging and CVD&#xD;
           risk. Temporal appearance of indices of cellular aging, ovarian aging and CVD risk would&#xD;
           support our primary hypothesis. Specifically, we propose to determine whether telomere&#xD;
           and mtDNA in peripheral leukocytes, oxidative stress (plasma F2-isoprostanes), and&#xD;
           indices of inflammation (C-reactive protein, interleukin-6, and soluble intercellular&#xD;
           adhesion molecule-1) correlate with both ovarian aging and CVD risk, and the temporal&#xD;
           pattern of appearance.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">August 15, 2018</start_date>
  <completion_date type="Anticipated">September 2, 2024</completion_date>
  <primary_completion_date type="Anticipated">February 2, 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Change in the EndoScore or reactive hyperemia ratio, an index of peripheral endothelial function, as assessed by the FDA-approved EndoPAT 2000</measure>
    <time_frame>2 times, once at each of 2 study visits ~1 year apart</time_frame>
    <description>Endothelium-mediated changes in vascular tone will be represented by the EndoScore or ratio of Reactive Hyperemia pre-occlusion to post-occlusion of the brachial artery (via blood pressure cuff). A score &gt; 1.67 is considered &quot;normal&quot; and a score &lt;= 1.67 is &quot;abnormal&quot;. The EndoPAT 2000 machine will be used for this measure, which is the only non-invasive method of measuring endothelial function or the state of arterial health. Well-functioning arteries protect blood vessels from hardening (or atherosclerosis) and plaque build up. The EndoScore score will be the primary measure for cardiovascular (CV) disease risk, as actual CV event rates will be too low for many years</description>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Anticipated">865</enrollment>
  <condition>Infertility</condition>
  <condition>Cardiovascular Risk Factor</condition>
  <arm_group>
    <arm_group_label>Women from original OVA cohort</arm_group_label>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      blood and urine&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        -  member of Northern California Kaiser Permanente Health Plan at time of enrollment into&#xD;
             original OVA cohort&#xD;
&#xD;
          -  self-identifying as Caucasian, Chinese, Filipino, African-American, or Hispanice&#xD;
             (Mexican or Central American)&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Enrollment into the original OVA cohort (NCT00501800)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Not a member of the original OVA cohort&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>35 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
  </eligibility>
  <overall_official>
    <last_name>Marcelle I Cedars, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of California, San Francisco</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California, San Francisco</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>January 25, 2019</study_first_submitted>
  <study_first_submitted_qc>January 29, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>September 6, 2022</last_update_submitted>
  <last_update_submitted_qc>September 6, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 7, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>reproductive health</keyword>
  <keyword>fertility</keyword>
  <keyword>infertility</keyword>
  <keyword>aging</keyword>
  <keyword>health</keyword>
  <keyword>cardiovascular disease</keyword>
  <keyword>cardiovascular disease risk</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infertility</mesh_term>
  </condition_browse>
  <!-- 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/NCT03825120
org study id: R01AG053332
secondary id: 1R01AG053332-01A1
nct id: NCT03825120
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Despite significant improvements in prevention and treatment of cardiovascular disease (CVD),
      the growing aging population suggests CVD will continue to pose a significant public health
      burden. Women are a special group where microvascular disease is more common and traditional
      risk factors may not fully identify risk. Women's reproductive history (e.g. menarcheal age,
      menstrual cycles, infertility, pregnancy, menopause) may pose unique risk and suggests an
      opportunity for new approaches. The investigators propose a women-centered approach for early
      identification of women at risk that investigates the unique loss of reproductive function at
      an age long before other vital systems fail. Despite its importance, little is known about
      the determinants or correlates of ovarian aging, or the health implications, especially in
      diverse communities. Only recently have reliable biomarkers of the remaining oocyte pool been
      available for use in normally cycling women. This availability gives us a unique opportunity
      to characterize the association between "ovarian age" (cross-sectional) and the rate of
      "ovarian aging" or oocyte decline over time (longitudinal) and the health implications of
      accelerated oocyte loss. The investigators hypothesize ovarian age/aging provides a window
      onto the general health of women. The investigators suggest it is not the progressive
      deficiency of estrogen with menopause that increases risk, but common underlying cellular
      aging mechanisms first evident in young populations as lower ovarian reserve (follicle
      number) due to the unique sensitivity of the ovary.

      Studies of cellular aging focused on mitochondrial dysfunction, oxidative stress,
      inflammation, and telomere length have identified correlations with CVD risk. Improved
      understanding of the mechanisms of cellular aging suggests telomere shortening and
      dysfunction may drive mitochondrial dysfunction and potentially the parallel between cellular
      aging and CVD. The oocyte is particularly sensitive to mitochondrial dysfunction, having 10
      times the number of mitochondria as any somatic cell. Additionally, mitochondrial dysfunction
      and telomere shortening have been associated with ovarian aging. This begs the question of
      whether, given the susceptibility of the ovary to mitochondrial dysfunction, accelerated
      ovarian aging may be a harbinger of subsequent CVD risk. To address this critical question,
      the investigators propose to leverage the largest and most ethnically diverse population of
      normal reproductive-aged women, with detailed measures of ovarian age, and to deploy
      peripheral endothelial function testing, a non-invasive sensitive marker of early CVD risk.
      Ovarian aging is thought to be largely genetically determined, but the impact of
      race/ethnicity has not been fully explored. Evaluating the impact of ethnicity on ovarian
      aging, and combining this information with the impact of modifiable behavioral risk factors,
      may help clarify CVD risk in young, ethnically-diverse, reproductive-age women. The
      investigators believe improving our understanding of factors that affect the rate of
      oocyte/follicle loss and the relationship with CVD risk factors will promote a novel method
      to identify women at earlier and/or increased cardiac risk.
The investigators propose to carry out three Specific Aims:

        1. Determine whether markers of ovarian age/aging are associated with increased CVD risk.

           Specifically, the investigators propose to assess whether:

             1. Ovarian age predicts CVD risk (measured by peripheral endothelial function testing)
                independent of chronological age.

             2. The rate of ovarian aging is independently associated with increased CVD risk after
                adjustment for ovarian and chronological age.

        2. Determine whether ovarian aging may moderate or mediate established associations between
           race/ethnicity and CVD risk and socio/emotional health and CVD risk. Specifically, the
           investigators propose to:

             1. Examine whether observed race/ethnic disparities in CVD risk (measured by
                peripheral endothelial function testing) may vary by (moderation model) or be
                partially attributable to (mediation model) ovarian aging.

             2. Examine whether effects of socio/emotional health (as indexed by separate
                composites of psychosocial functioning and socioeconomic status) on CVD risk may
                vary by (moderation model) or be partially attributable to (mediation model)
                ovarian aging.

        3. Determine if similar mechanisms of cellular aging underlie both ovarian aging and CVD
           risk. Temporal appearance of indices of cellular aging, ovarian aging and CVD risk would
           support our primary hypothesis. Specifically, we propose to determine whether telomere
           and mtDNA in peripheral leukocytes, oxidative stress (plasma F2-isoprostanes), and
           indices of inflammation (C-reactive protein, interleukin-6, and soluble intercellular
           adhesion molecule-1) correlate with both ovarian aging and CVD risk, and the temporal
           pattern of appearance.
observational model: Cohort
time perspective: Prospective
measure: Change in the EndoScore or reactive hyperemia ratio, an index of peripheral endothelial function, as assessed by the FDA-approved EndoPAT 2000
time frame: 2 times, once at each of 2 study visits ~1 year apart
description: Endothelium-mediated changes in vascular tone will be represented by the EndoScore or ratio of Reactive Hyperemia pre-occlusion to post-occlusion of the brachial artery (via blood pressure cuff). A score > 1.67 is considered "normal" and a score <= 1.67 is "abnormal". The EndoPAT 2000 machine will be used for this measure, which is the only non-invasive method of measuring endothelial function or the state of arterial health. Well-functioning arteries protect blood vessels from hardening (or atherosclerosis) and plaque build up. The EndoScore score will be the primary measure for cardiovascular (CV) disease risk, as actual CV event rates will be too low for many years
arm group label: Women from original OVA cohort
blood and urine
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 35 Years
maximum age: 55 Years
last name: Marcelle I Cedars, MD
role: Principal Investigator
affiliation: University of California, San Francisco
facility: 
country: United States
responsible party type: Sponsor
mesh term: Infertility