<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/NCT03035201</url>
  </required_header>
  <id_info>
    <org_study_id>IRB00037753</org_study_id>
    <secondary_id>1R01AG050657-01A1</secondary_id>
    <nct_id>NCT03035201</nct_id>
  </id_info>
  <brief_title>COcoa Supplement and Multivitamin Outcomes Study for the Mind</brief_title>
  <acronym>COSMOS-Mind</acronym>
  <official_title>COcoa Supplement and Multivitamin Outcomes Study-Mind</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Wake Forest University Health Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
    <collaborator>
      <agency>Brigham and Women's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Wake Forest University Health Sciences</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</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 parent trial (COcoa Supplement and Multivitamin Outcomes Study, COSMOS; NCT02422745) is a&#xD;
      randomized clinical trial of cocoa extract supplement (containing a total of 500 mg/d&#xD;
      flavanols, including 80 mg. (-)-epicatechins), and a standard multivitamin supplement to&#xD;
      reduce the risk of cardiovascular disease and cancer among men aged 60 years and older and&#xD;
      women aged 65 years and older. A cognitive ancillary study (COSMOS-Mind) is being conducted&#xD;
      among men and women, 65 years and older, who are enrolled in COSMOS and will examine whether&#xD;
      the cocoa extract supplement or the multivitamin supplement improves cognitive function and&#xD;
      reduces risk of cognitive impairment, including Alzheimer's disease (AD) and other related&#xD;
      types of dementia. Participants at the Wake Forest site will only be getting a phone call.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Identifying a safe, affordable, and well-tolerated intervention that prevents cognitive&#xD;
      decline in older adults is of critical public health importance. There is compelling evidence&#xD;
      from basic science, and small clinical studies that cocoa flavanols may protect cognitive&#xD;
      function in older adults and reduce risk of Alzheimer's disease (AD) and related dementia.&#xD;
      Thus, this intervention could have important downstream benefits for health care utilization&#xD;
      and cost, caregiver burden, and overall quality of life for older adults. Cocoa flavanol&#xD;
      effects on cognition, however, need to be assessed in a definitive clinical trial.&#xD;
&#xD;
      The parent trial (COSMOS) will enroll 21,442 women and men nationwide, drawn from the Women's&#xD;
      Health Initiative (WHI) participant cohort and the VITamin D and OmegA-3 TriaL (VITAL)&#xD;
      non-randomized respondent cohort, and will be conducted primarily by mail to assess whether&#xD;
      high-potency cocoa flavanol extract and a multivitamin - alone or in combination - will&#xD;
      reduce risk of cardiovascular disease and cancer over 3 years of follow-up.&#xD;
&#xD;
      After the COSMOS trial began, an advanced method to analyze cocoa flavanols was accredited by&#xD;
      Association of Official Agricultural Chemists (AOAC) International as a First Action Official&#xD;
      Method of Analysis https://doi.org/10.1093/jaoacint/qsaa132 [secure-web.cisco.com]). This&#xD;
      updated method relies on a reference material (RM8403) recently standardized and made&#xD;
      commercially available by the U.S. National Institute of Standards and Technology. While the&#xD;
      actual cocoa flavanol content of the COSMOS intervention remained unchanged throughout the&#xD;
      trial, the application of this new analytical method led to expected changes in how the total&#xD;
      cocoa flavanol content is now reported. Applying AOAC 2020.05/RM8403 to the COSMOS&#xD;
      intervention, the total cocoa flavanol content of the COSMOS intervention is now 500 mg/day.&#xD;
      Reporting of (-)-epicatechin content remained unaffected. Going forward, this record will&#xD;
      therefore apply AOAC 2020.05/RM8403 and report that the COSMOS intervention tested 500 mg/day&#xD;
      of cocoa flavanols, including 80 mg of (-)-epicatechin.&#xD;
&#xD;
      Once participants are enrolled in COSMOS, the study team at Brigham and Women's Hospital will&#xD;
      provide contact information and other parent trial outcomes for COSMOS-Mind participants to&#xD;
      the Wake Forest team using a secure web-based data transfer system. This seamless exchange of&#xD;
      information between sites will permit timely accounting to ensure that the targeted&#xD;
      demographics for enrollment are achieved (e.g. gender, age, race, ethnicity).&#xD;
&#xD;
      COSMOS-Mind will only be administered a telephone cognitive assessment to all participants at&#xD;
      enrollment (baseline), and annually for 3 years of follow-up by trained and certified staff&#xD;
      of the Wake Forest COSMOS-Mind team.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2016</start_date>
  <completion_date type="Actual">February 12, 2021</completion_date>
  <primary_completion_date type="Actual">February 12, 2021</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>Global Cognitive Function: Average Change Over Follow-up From Baseline</measure>
    <time_frame>From Baseline through Year 3</time_frame>
    <description>A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The primary comparison is for the margins of the factorial design: active cocoa flavonal (with or without active multivitamin) versus placebo flavonal (with or without active multivitamin).</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Composite Cognitive Function</measure>
    <time_frame>From baseline through year 3</time_frame>
    <description>A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The comparison for this secondary outcome is based on the margins of the factorial design to compare multivitamin (with or without cocoa flavonal) with multivitamin placebo (with or without cocoa flavonal)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incident Mild Cognitive Impairment</measure>
    <time_frame>From baseline through year 3</time_frame>
    <description>Mild cognitive impairment based on centralized adjudication of cognitive test scores and input from a proxy. Limited to participants free of mild cognitive impairment at baseline. Incidence over 3 years of follow-up.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence of Mild Cognitive Impairment Among Those Free at Baseline</measure>
    <time_frame>From baseline through year 3</time_frame>
    <description>Mild cognitive impairment based on central adjudication of test scores with input from proxies. Based on test scores administered annually across 3 years.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Executive Function</measure>
    <time_frame>From baseline through year 3</time_frame>
    <description>Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Linear contrast of scores collected at baseline, year 1, year 2, and year 3: (z1+z2+z3)/3 - z0)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Episodic Memory</measure>
    <time_frame>From baseline through year 3</time_frame>
    <description>Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. Annual test administrations.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Executive Function</measure>
    <time_frame>From baseline through year 3</time_frame>
    <description>Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Tests administered annually.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Episodic Memory</measure>
    <time_frame>From baseline through year 3</time_frame>
    <description>Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance.</description>
  </secondary_outcome>
  <number_of_groups>4</number_of_groups>
  <enrollment type="Actual">2262</enrollment>
  <condition>Cognitive Impairment</condition>
  <condition>Dementia</condition>
  <condition>Aging</condition>
  <arm_group>
    <arm_group_label>Cocoa extract + multivitamin (MTV)</arm_group_label>
    <description>2 capsules containing 500 mg/d cocoa extract; daily MTV</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cocoa extract + multivitamin placebo</arm_group_label>
    <description>2 capsules containing 500 mg/d cocoa extract; daily MTV placebo</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cocoa extract placebo + multivitamin</arm_group_label>
    <description>Cocoa extract placebo (2 capsules/d); daily MTV</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Cocoa extract placebo + multivitamin placebo</arm_group_label>
    <description>Cocoa extract placebo (2 capsules/d); daily MTV placebo</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        COSMOS-Mind will include 2,000 participants from the COSMOS parent trial who are at least&#xD;
        65 years of age, with approximately equal distribution of women and men.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Participants in COSMOS (NCT02422745) who meet the following criteria are eligible to&#xD;
        participate in this ancillary study:&#xD;
&#xD;
        Inclusion Criteria -&#xD;
&#xD;
          1. Men and women 65 years and older.&#xD;
&#xD;
          2. Willingness to participate.&#xD;
&#xD;
          3. Ability to answer questions by phone.&#xD;
&#xD;
        Exclusion Criteria -&#xD;
&#xD;
          1. Participants who are co-enrolled in the WHI Memory Study.&#xD;
&#xD;
          2. Participants with insulin-dependent diabetes.&#xD;
&#xD;
          3. Participants who are unable to complete the baseline cognitive assessments.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>65 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Laura D Baker, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mark A Espeland, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Wake Forest University Health Sciences</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Stephen R Rapp, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Co-Investigator Wake Forest School of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Sally A Shumaker, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Co-Investigator Wake Forest School of Medicine</affiliation>
  </overall_official>
  <overall_official>
    <last_name>JoAnn E Manson, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Parent Study Principal Investigator/COSMOS Mind Co-Investigator Brigham and Women's Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Howard Sesso, SCD, MPH</last_name>
    <role>Principal Investigator</role>
    <affiliation>Parent Study Principal Investigator/COSMOS Mind Co-Investigator Brigham and Women's Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Wake Forest School of Medicine</name>
      <address>
        <city>Winston-Salem</city>
        <state>North Carolina</state>
        <zip>27157</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.cosmostrial.org/</url>
    <description>COcoa Supplement and Multivitamin Outcomes Study</description>
  </link>
  <verification_date>May 2023</verification_date>
  <study_first_submitted>January 20, 2017</study_first_submitted>
  <study_first_submitted_qc>January 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 27, 2017</study_first_posted>
  <results_first_submitted>March 3, 2023</results_first_submitted>
  <results_first_submitted_qc>August 18, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">August 22, 2023</results_first_posted>
  <last_update_submitted>August 18, 2023</last_update_submitted>
  <last_update_submitted_qc>August 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Memory</keyword>
  <keyword>Mild Cognitive Impairment</keyword>
  <keyword>Alzheimer's Disease</keyword>
  <keyword>Cognition</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cognitive Dysfunction</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>COSMOS-Mind and COSMOS (parent trial, PI: Manson and Sesso) have data transfer procedures and protocols in place which use password protection and encryption, to permit seamless and secure exchange of information. Safety monitoring will be completed through the parent trial. The COSMOS-Mind staff will send all adverse events reported to them to the parent trial for reporting and follow-up. This data will be sent electronically only to approved users through a protected network.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_time_frame>after completion of study</ipd_time_frame>
    <ipd_access_criteria>Data have been submitted to the parent COSMOS trial for merging with phenotypes and distribution.</ipd_access_criteria>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>June 15, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/01/NCT03035201/Prot_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Statistical Analysis Plan</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>April 11, 2023</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/01/NCT03035201/SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Cocoa Extract + Multivitamin</title>
          <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver</description>
        </group>
        <group group_id="P2">
          <title>Cocoa Extract + Multivitamin Placebo</title>
          <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver placebo</description>
        </group>
        <group group_id="P3">
          <title>Cocoa Extract Placebo + Multivitamin</title>
          <description>Daily cocoa extract placebo Daily Centrum Silver</description>
        </group>
        <group group_id="P4">
          <title>Cocoa Extract Placebo + Multivitamin Placebo</title>
          <description>Daily cocoa extract placebo Daily Centrum Silver placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="571"/>
                <participants group_id="P2" count="553"/>
                <participants group_id="P3" count="551"/>
                <participants group_id="P4" count="587"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="444"/>
                <participants group_id="P2" count="441"/>
                <participants group_id="P3" count="441"/>
                <participants group_id="P4" count="462"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="127"/>
                <participants group_id="P2" count="112"/>
                <participants group_id="P3" count="110"/>
                <participants group_id="P4" count="125"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="9"/>
                <participants group_id="P2" count="12"/>
                <participants group_id="P3" count="9"/>
                <participants group_id="P4" count="10"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="51"/>
                <participants group_id="P2" count="49"/>
                <participants group_id="P3" count="37"/>
                <participants group_id="P4" count="46"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Lost to Follow-up</title>
              <participants_list>
                <participants group_id="P1" count="67"/>
                <participants group_id="P2" count="51"/>
                <participants group_id="P3" count="64"/>
                <participants group_id="P4" count="69"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Cocoa Extract + Multivitamin</title>
          <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver</description>
        </group>
        <group group_id="B2">
          <title>Cocoa Extract + Multivitamin Placebo</title>
          <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver placebo</description>
        </group>
        <group group_id="B3">
          <title>Cocoa Extract Placebo + Multivitamin</title>
          <description>Daily cocoa extract placebo Daily Centrum Silver</description>
        </group>
        <group group_id="B4">
          <title>Cocoa Extract Placebo + Multivitamin Placebo</title>
          <description>Daily cocoa extract placebo Daily Centrum Silver placebo</description>
        </group>
        <group group_id="B5">
          <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="571"/>
            <count group_id="B2" value="553"/>
            <count group_id="B3" value="551"/>
            <count group_id="B4" value="587"/>
            <count group_id="B5" value="2262"/>
          </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="72.7" spread="5.5"/>
                    <measurement group_id="B2" value="73.2" spread="5.6"/>
                    <measurement group_id="B3" value="72.9" spread="5.6"/>
                    <measurement group_id="B4" value="73.1" spread="5.7"/>
                    <measurement group_id="B5" value="73.0" spread="5.6"/>
                  </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="339"/>
                    <measurement group_id="B2" value="330"/>
                    <measurement group_id="B3" value="319"/>
                    <measurement group_id="B4" value="360"/>
                    <measurement group_id="B5" value="1348"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="232"/>
                    <measurement group_id="B2" value="223"/>
                    <measurement group_id="B3" value="232"/>
                    <measurement group_id="B4" value="227"/>
                    <measurement group_id="B5" value="914"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race/Ethnicity, Customized</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>American Indian/Alaska Native</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="13"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Asian/Pacific Islander</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="9"/>
                    <measurement group_id="B2" value="12"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="8"/>
                    <measurement group_id="B5" value="39"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Black/African American</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40"/>
                    <measurement group_id="B2" value="23"/>
                    <measurement group_id="B3" value="34"/>
                    <measurement group_id="B4" value="34"/>
                    <measurement group_id="B5" value="131"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Hispanic</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="21"/>
                    <measurement group_id="B5" value="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Multiracial/Unknown</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                    <measurement group_id="B5" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-Hispanic White</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="506"/>
                    <measurement group_id="B2" value="498"/>
                    <measurement group_id="B3" value="482"/>
                    <measurement group_id="B4" value="520"/>
                    <measurement group_id="B5" value="2006"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="571"/>
                    <measurement group_id="B2" value="553"/>
                    <measurement group_id="B3" value="551"/>
                    <measurement group_id="B4" value="587"/>
                    <measurement group_id="B5" value="2262"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Global Cognitive Composite</title>
          <description>The global composite is average of z-scores for each component. Each component has mean 0 at baseline, thus the composite z-score has mean 0. Individual component tests are 1) Telephone Interview for Cognitive Status-modified that measures global cognitive function, 2) Immediate and Delayed Story Recall tests for verbal memory, 3) Oral Trail Making Test for attention and executive function, 4) Verbal Fluency, 5) Number Span Test for attention and working memory, and 5) Digit Ordering Test for working memory. Higher positive scores reflect better performance. There are no clinical thresholds.</description>
          <units>z-scores</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="-0.01" spread="0.99"/>
                    <measurement group_id="B2" value="0.02" spread="1.00"/>
                    <measurement group_id="B3" value="0.05" spread="1.02"/>
                    <measurement group_id="B4" value="-0.05" spread="0.99"/>
                    <measurement group_id="B5" value="0.00" spread="1.00"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Global Cognitive Function: Average Change Over Follow-up From Baseline</title>
        <description>A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The primary comparison is for the margins of the factorial design: active cocoa flavonal (with or without active multivitamin) versus placebo flavonal (with or without active multivitamin).</description>
        <time_frame>From Baseline through Year 3</time_frame>
        <population>Intention to treat -- All enrolled participants</population>
        <group_list>
          <group group_id="O1">
            <title>Cocoa Extract + Multivitamin</title>
            <description>2 capsules containing 500 mg/d cocoa extract; daily MTV</description>
          </group>
          <group group_id="O2">
            <title>Cocoa Extract + Multivitamin Placebo</title>
            <description>2 capsules containing 500 mg/d cocoa extract; daily MTV placebo</description>
          </group>
          <group group_id="O3">
            <title>Cocoa Extract Placebo + Multivitamin</title>
            <description>Cocoa extract placebo (2 capsules/d); daily MTV</description>
          </group>
          <group group_id="O4">
            <title>Cocoa Extract Placebo + Multivitamin Placebo</title>
            <description>Cocoa extract placebo (2 capsules/d); daily MTV placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Global Cognitive Function: Average Change Over Follow-up From Baseline</title>
          <description>A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The primary comparison is for the margins of the factorial design: active cocoa flavonal (with or without active multivitamin) versus placebo flavonal (with or without active multivitamin).</description>
          <population>Intention to treat -- All enrolled participants</population>
          <units>score on a scale</units>
          <param>Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="571"/>
                <count group_id="O2" value="553"/>
                <count group_id="O3" value="551"/>
                <count group_id="O4" value="587"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.24" spread="0.02"/>
                    <measurement group_id="O2" value="0.15" spread="0.02"/>
                    <measurement group_id="O3" value="0.20" spread="0.02"/>
                    <measurement group_id="O4" value="0.15" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Marginal comparisons from a repeated measures model using a linear contrast to estimate the mean differences between baseline versus average values across follow-up.</groups_desc>
            <non_inferiority_type>Other</non_inferiority_type>
            <non_inferiority_desc>two-tailed test of the null hypothesis of no differences between groups.</non_inferiority_desc>
            <p_value>&lt;0.05</p_value>
            <p_value_desc>Not adjusted</p_value_desc>
            <method>Mixed Models Analysis</method>
            <param_type>Mean from linear contrast</param_type>
            <param_value>0.03</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.02</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.02</ci_lower_limit>
            <ci_upper_limit>0.08</ci_upper_limit>
            <estimate_desc>Marginal effect of cocoa flavonal versus cocoa placebo based on the mean difference between linear contrasts.</estimate_desc>
            <other_analysis_desc>Wald test of a linear contrast from the mixed effects analysis....see protocol.</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Composite Cognitive Function</title>
        <description>A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The comparison for this secondary outcome is based on the margins of the factorial design to compare multivitamin (with or without cocoa flavonal) with multivitamin placebo (with or without cocoa flavonal)</description>
        <time_frame>From baseline through year 3</time_frame>
        <population>Complete randomized cohort</population>
        <group_list>
          <group group_id="O1">
            <title>Cocoa Extract + Multivitamin</title>
            <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver</description>
          </group>
          <group group_id="O2">
            <title>Cocoa Extract + Multivitamin Placebo</title>
            <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver placebo</description>
          </group>
          <group group_id="O3">
            <title>Cocoa Extract Placebo + Multivitamin</title>
            <description>Daily cocoa extract placebo Daily Centrum Silver</description>
          </group>
          <group group_id="O4">
            <title>Cocoa Extract Placebo + Multivitamin Placebo</title>
            <description>Daily cocoa extract placebo Daily Centrum Silver placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Composite Cognitive Function</title>
          <description>A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The comparison for this secondary outcome is based on the margins of the factorial design to compare multivitamin (with or without cocoa flavonal) with multivitamin placebo (with or without cocoa flavonal)</description>
          <population>Complete randomized cohort</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="571"/>
                <count group_id="O2" value="553"/>
                <count group_id="O3" value="551"/>
                <count group_id="O4" value="587"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.24" spread="0.02"/>
                    <measurement group_id="O2" value="0.15" spread="0.02"/>
                    <measurement group_id="O3" value="0.20" spread="0.02"/>
                    <measurement group_id="O4" value="0.15" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
              <group_id>O3</group_id>
              <group_id>O4</group_id>
            </group_id_list>
            <groups_desc>Marginal comparisons from a repeated measures model using a linear contrast to estimate the mean differences between baseline versus average values across follow-up.</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>two-tailed test of the null hypothesis of no differences between groups.</non_inferiority_desc>
            <p_value>&lt;0.05</p_value>
            <p_value_desc>Not adjusted</p_value_desc>
            <method>Wald test</method>
            <param_type>Mean difference of linear contrasts</param_type>
            <param_value>0.07</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.02</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.02</ci_lower_limit>
            <ci_upper_limit>0.12</ci_upper_limit>
            <estimate_desc>Marginal effects of multivitamin versus multivitamin placebo</estimate_desc>
            <other_analysis_desc>Wald test of a linear contrast from the mixed effects analysis....see protocol</other_analysis_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incident Mild Cognitive Impairment</title>
        <description>Mild cognitive impairment based on centralized adjudication of cognitive test scores and input from a proxy. Limited to participants free of mild cognitive impairment at baseline. Incidence over 3 years of follow-up.</description>
        <time_frame>From baseline through year 3</time_frame>
        <population>Limited to participants free of mild cognitive impairment at baseline. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
        <group_list>
          <group group_id="O1">
            <title>Cocoa Extract</title>
            <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine)</description>
          </group>
          <group group_id="O2">
            <title>Cocoa Extract Placebo</title>
            <description>Daily cocoa extract placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Incident Mild Cognitive Impairment</title>
          <description>Mild cognitive impairment based on centralized adjudication of cognitive test scores and input from a proxy. Limited to participants free of mild cognitive impairment at baseline. Incidence over 3 years of follow-up.</description>
          <population>Limited to participants free of mild cognitive impairment at baseline. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="916"/>
                <count group_id="O2" value="940"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="47"/>
                    <measurement group_id="O2" value="63"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Proportional hazards regression -- unadjusted two-sided test</non_inferiority_desc>
            <p_value>0.15</p_value>
            <p_value_desc>Not adjusted</p_value_desc>
            <method>Regression, Cox</method>
            <param_type>Hazard Ratio (HR)</param_type>
            <param_value>0.76</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.52</ci_lower_limit>
            <ci_upper_limit>1.11</ci_upper_limit>
            <estimate_desc>Comparison group is placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Incidence of Mild Cognitive Impairment Among Those Free at Baseline</title>
        <description>Mild cognitive impairment based on central adjudication of test scores with input from proxies. Based on test scores administered annually across 3 years.</description>
        <time_frame>From baseline through year 3</time_frame>
        <population>Participants free of mild cognitive impairment at baseline. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
        <group_list>
          <group group_id="O1">
            <title>Multivitamin</title>
            <description>Daily multivitamin</description>
          </group>
          <group group_id="O2">
            <title>Multivitamin Placebo</title>
            <description>Daily multivitamin placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Incidence of Mild Cognitive Impairment Among Those Free at Baseline</title>
          <description>Mild cognitive impairment based on central adjudication of test scores with input from proxies. Based on test scores administered annually across 3 years.</description>
          <population>Participants free of mild cognitive impairment at baseline. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="920"/>
                <count group_id="O2" value="936"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="53"/>
                    <measurement group_id="O2" value="57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Unadjusted 2-sided test</non_inferiority_desc>
            <p_value>0.62</p_value>
            <p_value_desc>Unadjusted</p_value_desc>
            <method>Regression, Cox</method>
            <param_type>Cox Proportional Hazard</param_type>
            <param_value>0.91</param_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.63</ci_lower_limit>
            <ci_upper_limit>1.32</ci_upper_limit>
            <estimate_desc>Comparison group is placebo.</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Executive Function</title>
        <description>Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Linear contrast of scores collected at baseline, year 1, year 2, and year 3: (z1+z2+z3)/3 - z0)</description>
        <time_frame>From baseline through year 3</time_frame>
        <population>All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
        <group_list>
          <group group_id="O1">
            <title>Cocoa Extract</title>
            <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine)</description>
          </group>
          <group group_id="O2">
            <title>Cocoa Extract Placebo</title>
            <description>Daily cocoa extract placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Executive Function</title>
          <description>Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Linear contrast of scores collected at baseline, year 1, year 2, and year 3: (z1+z2+z3)/3 - z0)</description>
          <population>All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1144"/>
                <count group_id="O2" value="1138"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.06" spread="0.02"/>
                    <measurement group_id="O2" value="0.04" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>Cocoa Flavonal minus Placebo</non_inferiority_desc>
            <p_value>0.24</p_value>
            <p_value_desc>Unadjusted</p_value_desc>
            <method>Mixed Models Analysis</method>
            <method_desc>Wald test comparing linear contrasts</method_desc>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.03</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.03</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.02</ci_lower_limit>
            <ci_upper_limit>0.08</ci_upper_limit>
            <estimate_desc>Cocoa Flavonal minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Episodic Memory</title>
        <description>Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. Annual test administrations.</description>
        <time_frame>From baseline through year 3</time_frame>
        <population>In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
        <group_list>
          <group group_id="O1">
            <title>Cocoa Extract</title>
            <description>Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine)</description>
          </group>
          <group group_id="O2">
            <title>Cocoa Extract Placebo</title>
            <description>Daily cocoa extract placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Episodic Memory</title>
          <description>Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. Annual test administrations.</description>
          <population>In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1144"/>
                <count group_id="O2" value="1138"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.29" spread="0.02"/>
                    <measurement group_id="O2" value="0.27" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Unadjusted 2-tailed test</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>two-sided</non_inferiority_desc>
            <p_value>0.41</p_value>
            <p_value_desc>Unadjusted</p_value_desc>
            <method>Mixed Models Analysis</method>
            <method_desc>Comparison of linear contrasts: cocoa flavonal minus placebo</method_desc>
            <param_type>Median Difference (Final Values)</param_type>
            <param_value>0.03</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.03</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>-0.04</ci_lower_limit>
            <ci_upper_limit>0.09</ci_upper_limit>
            <estimate_desc>Cocoa flavonal minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Executive Function</title>
        <description>Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Tests administered annually.</description>
        <time_frame>From baseline through year 3</time_frame>
        <population>All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
        <group_list>
          <group group_id="O1">
            <title>Multivitamin</title>
            <description>Daily multivitamin</description>
          </group>
          <group group_id="O2">
            <title>Multivitamin Placebo</title>
            <description>Daily multivitamin placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Executive Function</title>
          <description>Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Tests administered annually.</description>
          <population>All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1128"/>
                <count group_id="O2" value="1140"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.08" spread="0.02"/>
                    <measurement group_id="O2" value="0.02" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <groups_desc>2-sided test, unadjusted</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>2 sided test, multivitamin minus placebo</non_inferiority_desc>
            <p_value>0.02</p_value>
            <p_value_desc>Unadjusted</p_value_desc>
            <method>Mixed Models Analysis</method>
            <method_desc>Comparison of linear contrasts</method_desc>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.06</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.03</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.01</ci_lower_limit>
            <ci_upper_limit>0.11</ci_upper_limit>
            <estimate_desc>Multivitamin minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Episodic Memory</title>
        <description>Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance.</description>
        <time_frame>From baseline through year 3</time_frame>
        <population>All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
        <group_list>
          <group group_id="O1">
            <title>Multivitamin</title>
            <description>Daily multivitamin</description>
          </group>
          <group group_id="O2">
            <title>Multivitamin Placebo</title>
            <description>Daily multivitamin placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Episodic Memory</title>
          <description>Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance.</description>
          <population>All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan.</population>
          <units>score on a scale</units>
          <param>Least Squares Mean</param>
          <dispersion>Standard Error</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1128"/>
                <count group_id="O2" value="1140"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.31" spread="0.02"/>
                    <measurement group_id="O2" value="0.25" spread="0.02"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>Multivitamin minus placebo</groups_desc>
            <non_inferiority_type>Equivalence</non_inferiority_type>
            <non_inferiority_desc>2-sided, unadjusted</non_inferiority_desc>
            <p_value>0.04</p_value>
            <p_value_desc>Unadjusted</p_value_desc>
            <method>Mixed Models Analysis</method>
            <method_desc>Comparison of linear contrasts</method_desc>
            <param_type>Mean Difference (Net)</param_type>
            <param_value>0.06</param_value>
            <dispersion_type>Standard Error of the Mean</dispersion_type>
            <dispersion_value>0.03</dispersion_value>
            <ci_percent>95</ci_percent>
            <ci_n_sides>2-Sided</ci_n_sides>
            <ci_lower_limit>0.002</ci_lower_limit>
            <ci_upper_limit>0.126</ci_upper_limit>
            <estimate_desc>Multivitamin minus placebo</estimate_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Across all follow-up -- 3 years.</time_frame>
      <desc>Mortality was collected by the parent trial and passed on to us. Adverse events were collected and published by the parent COSMOS trial, but were not separately passed on to us. Per instructions from the reviewer, because mortality was not collected by COSMOS-Mind, we now do not report it in this document.</desc>
      <group_list>
        <group group_id="E1">
          <title>Cocoa Extract + Multivitamin</title>
          <description>2 capsules containing 500 mg/d cocoa extract; daily MTV</description>
        </group>
        <group group_id="E2">
          <title>Cocoa Extract + Multivitamin Placebo</title>
          <description>2 capsules containing 500 mg/d cocoa extract; daily MTV placebo</description>
        </group>
        <group group_id="E3">
          <title>Cocoa Extract Placebo + Multivitamin</title>
          <description>Cocoa extract placebo (2 capsules/d); daily MTV</description>
        </group>
        <group group_id="E4">
          <title>Cocoa Extract Placebo + Multivitamin Placebo</title>
          <description>Cocoa extract placebo (2 capsules/d); daily MTV placebo</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="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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>Mark Espeland, PhD; Multiple Principal Investigator</name_or_title>
      <organization>Wake Forest University School of Medicine</organization>
      <phone>336-716-2826</phone>
      <email>mespelan@wakehealth.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/NCT03035201
org study id: IRB00037753
secondary id: 1R01AG050657-01A1
nct id: NCT03035201
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
The parent trial (COcoa Supplement and Multivitamin Outcomes Study, COSMOS; NCT02422745) is a
      randomized clinical trial of cocoa extract supplement (containing a total of 500 mg/d
      flavanols, including 80 mg. (-)-epicatechins), and a standard multivitamin supplement to
      reduce the risk of cardiovascular disease and cancer among men aged 60 years and older and
      women aged 65 years and older. A cognitive ancillary study (COSMOS-Mind) is being conducted
      among men and women, 65 years and older, who are enrolled in COSMOS and will examine whether
      the cocoa extract supplement or the multivitamin supplement improves cognitive function and
      reduces risk of cognitive impairment, including Alzheimer's disease (AD) and other related
      types of dementia. Participants at the Wake Forest site will only be getting a phone call.
Identifying a safe, affordable, and well-tolerated intervention that prevents cognitive
      decline in older adults is of critical public health importance. There is compelling evidence
      from basic science, and small clinical studies that cocoa flavanols may protect cognitive
      function in older adults and reduce risk of Alzheimer's disease (AD) and related dementia.
      Thus, this intervention could have important downstream benefits for health care utilization
      and cost, caregiver burden, and overall quality of life for older adults. Cocoa flavanol
      effects on cognition, however, need to be assessed in a definitive clinical trial.

      The parent trial (COSMOS) will enroll 21,442 women and men nationwide, drawn from the Women's
      Health Initiative (WHI) participant cohort and the VITamin D and OmegA-3 TriaL (VITAL)
      non-randomized respondent cohort, and will be conducted primarily by mail to assess whether
      high-potency cocoa flavanol extract and a multivitamin - alone or in combination - will
      reduce risk of cardiovascular disease and cancer over 3 years of follow-up.

      After the COSMOS trial began, an advanced method to analyze cocoa flavanols was accredited by
      Association of Official Agricultural Chemists (AOAC) International as a First Action Official
      Method of Analysis https://doi.org/10.1093/jaoacint/qsaa132 [secure-web.cisco.com]). This
      updated method relies on a reference material (RM8403) recently standardized and made
      commercially available by the U.S. National Institute of Standards and Technology. While the
      actual cocoa flavanol content of the COSMOS intervention remained unchanged throughout the
      trial, the application of this new analytical method led to expected changes in how the total
      cocoa flavanol content is now reported. Applying AOAC 2020.05/RM8403 to the COSMOS
      intervention, the total cocoa flavanol content of the COSMOS intervention is now 500 mg/day.
      Reporting of (-)-epicatechin content remained unaffected. Going forward, this record will
      therefore apply AOAC 2020.05/RM8403 and report that the COSMOS intervention tested 500 mg/day
      of cocoa flavanols, including 80 mg of (-)-epicatechin.

      Once participants are enrolled in COSMOS, the study team at Brigham and Women's Hospital will
      provide contact information and other parent trial outcomes for COSMOS-Mind participants to
      the Wake Forest team using a secure web-based data transfer system. This seamless exchange of
      information between sites will permit timely accounting to ensure that the targeted
      demographics for enrollment are achieved (e.g. gender, age, race, ethnicity).

      COSMOS-Mind will only be administered a telephone cognitive assessment to all participants at
      enrollment (baseline), and annually for 3 years of follow-up by trained and certified staff
      of the Wake Forest COSMOS-Mind team.
observational model: Cohort
time perspective: Prospective
measure: Global Cognitive Function: Average Change Over Follow-up From Baseline
time frame: From Baseline through Year 3
description: A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The primary comparison is for the margins of the factorial design: active cocoa flavonal (with or without active multivitamin) versus placebo flavonal (with or without active multivitamin).
measure: Composite Cognitive Function
time frame: From baseline through year 3
description: A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The comparison for this secondary outcome is based on the margins of the factorial design to compare multivitamin (with or without cocoa flavonal) with multivitamin placebo (with or without cocoa flavonal)
measure: Incident Mild Cognitive Impairment
time frame: From baseline through year 3
description: Mild cognitive impairment based on centralized adjudication of cognitive test scores and input from a proxy. Limited to participants free of mild cognitive impairment at baseline. Incidence over 3 years of follow-up.
measure: Incidence of Mild Cognitive Impairment Among Those Free at Baseline
time frame: From baseline through year 3
description: Mild cognitive impairment based on central adjudication of test scores with input from proxies. Based on test scores administered annually across 3 years.
measure: Executive Function
time frame: From baseline through year 3
description: Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Linear contrast of scores collected at baseline, year 1, year 2, and year 3: (z1+z2+z3)/3 - z0)
measure: Episodic Memory
time frame: From baseline through year 3
description: Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. Annual test administrations.
measure: Executive Function
time frame: From baseline through year 3
description: Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Tests administered annually.
measure: Episodic Memory
time frame: From baseline through year 3
description: Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance.
arm group label: Cocoa extract + multivitamin (MTV)
description: 2 capsules containing 500 mg/d cocoa extract; daily MTV
arm group label: Cocoa extract + multivitamin placebo
description: 2 capsules containing 500 mg/d cocoa extract; daily MTV placebo
arm group label: Cocoa extract placebo + multivitamin
description: Cocoa extract placebo (2 capsules/d); daily MTV
arm group label: Cocoa extract placebo + multivitamin placebo
description: Cocoa extract placebo (2 capsules/d); daily MTV placebo
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 65 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Laura D Baker, PhD
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
last name: Mark A Espeland, PhD
role: Principal Investigator
affiliation: Wake Forest University Health Sciences
last name: Stephen R Rapp, PhD
role: Principal Investigator
affiliation: Co-Investigator Wake Forest School of Medicine
last name: Sally A Shumaker, PhD
role: Principal Investigator
affiliation: Co-Investigator Wake Forest School of Medicine
last name: JoAnn E Manson, MD
role: Principal Investigator
affiliation: Parent Study Principal Investigator/COSMOS Mind Co-Investigator Brigham and Women's Hospital
last name: Howard Sesso, SCD, MPH
role: Principal Investigator
affiliation: Parent Study Principal Investigator/COSMOS Mind Co-Investigator Brigham and Women's Hospital
facility: 
country: United States
url: http://www.cosmostrial.org/
description: COcoa Supplement and Multivitamin Outcomes Study
responsible party type: Sponsor
mesh term: Cognitive Dysfunction
sharing ipd: Yes
ipd description: COSMOS-Mind and COSMOS (parent trial, PI: Manson and Sesso) have data transfer procedures and protocols in place which use password protection and encryption, to permit seamless and secure exchange of information. Safety monitoring will be completed through the parent trial. The COSMOS-Mind staff will send all adverse events reported to them to the parent trial for reporting and follow-up. This data will be sent electronically only to approved users through a protected network.
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd time frame: after completion of study
ipd access criteria: Data have been submitted to the parent COSMOS trial for merging with phenotypes and distribution.
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 