AS355 - Randomized trial of cocoa extract and multivitamins for CVD and cancer prevention

Investigator Names and Contact Information

JoAnn Manson (jmanson@rics.bwh.harvard.edu)

Howie Sesso

Introduction/Intent

The COcoa Supplement and Multivitamin Outcomes Study (COSMOS) is a randomized, double-blind, placebo-controlled, 2x2 factorial trial of a high-quality cocoa extract supplement (containing 600 mg/d flavanols, including 80 mg (-)-epicatechins), and a multivitamin supplement to reduce the risk of cardiovascular disease (CVD) and cancer in 12,000 women aged ≥65 years and 6,000 men aged ≥60 years with 4 years of treatment and follow-up. These promising interventions have both already shown favorable results in observational studies and randomized trials, and are well-tolerated, safe, and relatively inexpensive. For cocoa flavanols, several small randomized trials have demonstrated benefits for intermediate outcomes, including blood pressure, lipids, insulin sensitivity, and flow-mediated vasodilation; for multivitamins, a prior large-scale randomized trial in men showed a significant reduction in cancer, but trial data in women are lacking. For both interventions, a confirmatory large-scale randomized trial such as the COSMOS in women and men could have major clinical and public health implications.

WHI CCC COSMOS staffThe trial utilizes an innovative and highly time- and cost- efficient approach leveraging the existing infrastructure of the Women's Health Initiative (WHI) and the VITamin D and OmegA-3 TriaL (VITAL). After an initial screening contact by the WHI, the Brigham and Women's Hospital (BWH) will recruit and consent into COSMOS 12,000 women among active WHI Extension Study participants who have demonstrated a commitment to scientific research and are free of baseline CVD, and free of cancer diagnosed within the last 2 years. BWH will recruit an additional 6,000 men among non-randomized respondents of the VITAL who expressed interest in research studies and already reported preliminary eligibility information. Thus, a total of 18,000 women and men will be randomized into the COSMOS trial. The study plan involves recruitment over one year, including a placebo run-in, and 4 years of intervention and outcome ascertainment that will provide sufficient power to detect small-to-moderate reductions in primary CVD and cancer outcomes. The trial will be conducted primarily by mail, with study pills mailed by BWH to participants and CVD and cancer outcomes confirmed by medical record review. Existing WHI resources provide follow-up for ascertainment of self-reported health events and adjudication of cancer endpoints in all WHI participants, and for CVD outcomes in a subcohort. COSMOS will expand this to include adjudication of all CVD outcomes for those randomized into the COSMOS. We will also leverage the blood collected in the ongoing WHI Long Life Study, which provide pre-randomization baseline bloods with completed biomarker and genomic data in a subsample of the COSMOS. In 1,000 WHI women and in 500 VITAL male respondents with baseline bloods, BWH will collect 2-year follow-up bloods to assess changes in important nutritional and vascular/metabolic biomarkers related to our cocoa flavanols and multivitamin interventions. The design of the trial also allows for the development of multiple ancillary studies, including collection of information on secondary outcomes and studies utilizing follow-up home-based visits and/or in-clinic visits at Clinical and Translational Science Centers.

COSMOS Trial PIs: Dr. JoAnn Manson and Dr. Howard Sesso at Brigham and Women's Hospital, Harvard Medical School, and Dr. Garnet Anderson at the WHI CCC, Fred Hutchinson Cancer Research Center

Primary Hypotheses:

1. Cocoa extract (2 capsules/day containing a total of 600 mg/d flavanols, including 80 mg (-)-epicatechin, and 50 mg theobromine) will reduce the risk of major cardiovascular events, defined for these purposes as a composite endpoint of MI, 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 MI, 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 1,000 women already providing baseline bloods for the WHI Long Life Study and 500 VITAL male respondents who will provide baseline bloods, cocoa extract and/or a daily multivitamin will significantly change levels of blood flavonoids, other pertinent nutritional biomarkers, and vascular/metabolic biomarkers 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.