COcoa Supplement and Multivitamin Outcomes Study

The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a randomized clinical trial
of cocoa extract supplement (containing a total of 600 mg/d flavanols, including 80 mg.
(-)-epicatechins), and a standard multivitamin supplement to reduce the risk of
cardiovascular disease and cancer among women aged 65 years and older and men aged 60 years
and older.

Participants in COSMOS were recruited from among Women's Health Initiative (WHI) Extension
Study cohort members; non-randomized respondents to mailings for the VITamin D and OmegA-3
TriaL (VITAL); respondents to nationwide invitational mailings to age-eligible adults; and
volunteers who learned about the trial through the media or through ResearchMatch.org, an
electronic recruitment website.

Several small randomized trials have demonstrated benefits for cocoa flavanols on
intermediate outcomes, including blood pressure, lipids, insulin sensitivity, and
flow-mediated vasodilation. For multivitamins, a prior large-scale randomized trial in
middle-aged and older men showed a significant reduction in cancer, but comparable trial data
in women are lacking. For both interventions, a large-scale clinical trial such as COSMOS
could have major clinical and public health implications.

Eligible participants have been assigned by chance (like a coin toss) to one of four groups:
(1) daily cocoa extract and multivitamin; (2) daily cocoa extract and multivitamin placebo;
(3) daily cocoa extract placebo and multivitamin; or (4) daily cocoa extract placebo and
multivitamin placebo. Participants have an equal chance of being assigned to any of these
four groups and a 3 out of 4 chance of receiving at least one active agent.

Participants in all groups take three pills each day: two capsules that contain either cocoa
extract or cocoa extract placebo, and one tablet that contains either multivitamin or
multivitamin placebo. Participants receive their study pills in convenient calendar packs via
U.S. mail.

Participants are asked to complete mailed questionnaires each year. The questionnaires ask
about health; lifestyle habits, such as diet, physical activity, and smoking; use of
medications and dietary supplements; family history of illness and new medical diagnoses.
Occasionally, participants may receive a phone call from study staff to collect information
or clarify responses on the questionnaires.

At baseline, approximately 7,000 COSMOS participants provided optional blood and urine
samples, which will be used to determine whether the study agents significantly change
biomarkers and other risk factors related to cardiovascular disease and cancer. Selected
participants either have specimens collected through mailed specimen collection kits that are
returned by the participant, or have blood, urine, blood pressure, and anthropometric
measurements collected by technicians from Examination Management Services, Inc. (EMSI), a
national clinical services provider. A subgroup of those who provide baseline specimens and
measurements are asked to provide follow-up samples and measurements.

At baseline and after each year of follow-up, approximately 4,000 COSMOS participants
complete web-based assessments of cognitive function. During the trial, participants will
complete up to 4 assessments, each of which takes approximately 25 minutes to complete. The
trial will assess whether the study agents significantly affect change in cognitive function
over time.

At baseline and year 2 of the trial, approximately 600 participants living within driving
distance of Boston, Massachusetts provide additional measurements from in-clinic study visits
at the Clinical and Translational Science Center (CTSC) of Brigham and Women's Hospital.
These visits include cognitive function assessments, anthropometrics, physical function
assessments, blood pressure and other measurements. The trial will assess whether the study
agents significantly affect changes in these variables over time.

Primary Hypotheses:

1. A cocoa extract supplement will reduce the risk of major cardiovascular events, defined
as a composite endpoint of myocardial infarction, stroke, cardiovascular mortality, and
coronary revascularization;

2. A daily multivitamin will reduce the risk of invasive cancer (excluding non-melanoma
skin cancer).

Secondary Hypotheses:

1. Cocoa extract will reduce the risk of invasive cancer (excluding non-melanoma skin
cancer);

2. A daily multivitamin will reduce the risk of major cardiovascular events;

3. Cocoa extract and/or a daily multivitamin will reduce the combined endpoint of major
cardiovascular events plus all-cause mortality;

4. Cocoa extract and/or a daily multivitamin will reduce the risk of individual
cardiovascular events, including myocardial infarction, stroke, cardiovascular
mortality, coronary revascularization, and total mortality; plus site-specific cancers,
including breast, colorectal, and lung cancer;

5. A daily multivitamin will reduce the risk of cancer among women and men with a history
of cancer at baseline;

6. In a subset of equal numbers of female and male COSMOS respondents who provide baseline
bloods, cocoa extract and/or a daily multivitamin will significantly change levels of
blood flavonoids from baseline to 2 years of follow-up.

Tertiary Aim:

To assess whether the cocoa extract and/or a daily multivitamin exhibit synergistic effects
on risk of major cardiovascular events or cancer, and if the effects vary by nutritional
status or medication use.

Aims of Clinical and Translational Science Center (CTSC) Component:

To test whether the cocoa extract and/or a daily multivitamin has beneficial effects on:

1. Systolic and diastolic blood pressure;

2. Pulse wave velocity (PWV) and central blood pressure indices as measured by pulse wave
analysis;

3. Cognitive function and memory;

4. Physical performance as assessed by balance tests, grip strength, timed chair stands,
and walking speed,

5. Bone loss in the spine, hip and total body as assessed by bone-mineral density (BMD) and
changes in body composition as assessed by dual x-ray absorpiometry (DXA);

6. Metabolic and functional changes within the hippocampus using cerebral blood volume
(CBV) MRI.

Inclusion Criteria:

1. Women ≥ 65 years of age participating in the Women's Health Initiative (WHI) Extension
Study.

2. Men ≥ 60 years of age and women age ≥ 65 years of age who were contacted for but not
randomized into the VITAL trial.

3. Other women ≥ 65 years of age and men aged ≥ 60 years of age who responded to targeted
mass mailings and volunteers who learned about the trial through the media or through
ResearchMatch.org, an electronic recruitment website.

4. Willing to participate, as evidenced by providing informed consent and completing all
required baseline forms.

Exclusion Criteria:

1. History of myocardial infarction or stroke.

2. Diagnosed with invasive cancer other than non-melanoma skin cancer in the last 2 years
prior to enrollment.

3. Any serious illness that would preclude participation and/or completion of the trial,
including the diagnosis of kidney failure and current dialysis treatment.

4. Taking cocoa extract or multivitamin supplements and not willing to forego use during
the trial.

5. Taking total supplemental vitamin D > 1,000 IU/day and not willing to forego use
during the trial.

6. Taking total supplemental calcium > 1,200 mg/day and not willing to forego use during
the trial.

7. Extreme sensitivity to caffeine.

8. Consume < 75% of the expected number of both types of supplements during the run-in
phase.

9. Unable to communicate in English due to language barrier or mental incapacity.