COcoa Supplement and Multivitamin Outcomes Study

The purpose of this study is to determine whether taking daily, dietary supplements of cocoa extract (containing cocoa flavanols and theobromine from the cocoa bean) and/or a standard multivitamin reduces the risk of developing cardiovascular disease (including heart attack, stroke, coronary revascularization, unstable angina or acute coronary syndrome (ACS) requiring hospitalization, carotid artery surgery, and peripheral artery surgery or angioplasty, and cardiovascular mortality) and cancer.

The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a randomized clinical trial of cocoa extract supplement (containing a total of 600 mg/d cocoa 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.

After the COSMOS trial began, an advanced method to analyze cocoa flavanols was accredited by AOAC International as a First Action Official Method of Analysis (https://doi.org/10.1093/jaoacint/qsaa132). 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, we 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.

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.

The expected rates for our original primary composite cardiovascular disease (CVD) endpoint were based on the projected age and sex distribution of the trial cohort and CVD event rates from our previously conducted trials. However, we determined that the observed rates of CVD endpoints among COSMOS participants were lower than expected due to a younger population of women, increasing use of statins and other pharmacotherapies as seen in other recently published clinical trials, and the impact of COVID-19 on fewer reports of CVD diagnoses, hospitalizations, and procedures. As a result, the COSMOS Data and Safety Monitoring Board (DSMB) approved a proposal to add three new outcomes to our primary composite CVD endpoint: (1) unstable angina or acute coronary syndrome requiring hospitalization, (2) carotid artery surgery, and (3) peripheral artery surgery or angioplasty. These additional CVD outcomes are consistent with the atherosclerotic mechanisms underlying the postulated effects for the randomized interventions. COSMOS participants have already provided self-reports of these diagnoses since the start of the COSMOS trial that will be adjudicated via medical records. The original primary composite CVD endpoint will still be evaluated as a secondary outcome.

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 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, coronary revascularization, unstable angina or ACS requiring hospitalization, carotid artery surgery, and peripheral artery surgery or angioplasty;
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 a composite endpoint of MI, stroke, cardiovascular mortality, and coronary revascularization;
2. Cocoa extract will reduce the risk of invasive cancer (excluding non-melanoma skin cancer);
3. A daily multivitamin will reduce the risk of major cardiovascular events;
4. Cocoa extract and/or a daily multivitamin will reduce the combined endpoint of major cardiovascular events plus all-cause mortality;
5. Cocoa extract and/or a daily multivitamin will reduce the risk of individual cardiovascular events, including myocardial infarction, stroke, cardiovascular mortality, coronary revascularization, unstable angina or ACS requiring hospitalization, carotid artery surgery, and peripheral artery surgery or angioplasty, and total mortality; plus site-specific cancers, including breast, colorectal, and lung cancer;
6. A daily multivitamin will reduce the risk of cancer among women and men with a history of cancer at baseline;
7. In a subset of equal numbers of female and male COSMOS respondents who provide baseline bloods and/or urine samples, cocoa extract and/or a daily multivitamin will significantly change blood and/or urinary levels of flavonoids or their metabolites from baseline to 1, 2, or 3 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);

Eligibility Criteria:
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.