COcoa Supplement and Multivitamin Outcomes Study
Phase: PHASE4
Conditions: Cardiovascular Disease, Cancer
Sponsor: Brigham and Women's Hospital

 
 
 
 
 
COcoa Supplement and Multivitamin Outcomes Study 
(COSMOS) 
 
 
 
Study Protocol 
 
ClinicalTrials.gov Identifier: NCT02422745 
Date of Document: April 1, 2024 
 
 
 
 
 
 
 

COSMOS Protocol 
April 1, 2024 
Page 2 
The COcoa Supplement and Multivitamin Outcomes Study  
(COSMOS) Trial Protocol 
 
 
 
 
Investigators:  
JoAnn E. Manson, MD, DrPH and Howard D. Sesso, ScD, MPH, Brigham and Women’s Hospital 
Garnet L. Anderson, PhD, Fred Hutchinson Cancer Research Center 
 
Version 21  April 1, 2024 
 
 
Infrastructure support provided by an investigator-initiated grant from Mars Symbioscience. 
Cocoa Extract supplements and matching placebo provided by Mars Symbioscience. 
Multivitamins and matching placebo provided by Pfizer Inc. 
Partial infrastructure support provided through the National Heart Lung and Blood Institute’s funding for the 
Women’s Health Initiative Clinical Coordinating Center and Regional Center contracts. 
 
 
 
 

COSMOS Protocol 
April 1, 2024 
Page 3 
Table of Contents 
Section 
Topic 
Page 
1.0. 
Overview 
4 
2.0. 
Study Objectives 
5 
2.1. 
 
Primary Hypotheses 
5 
2.2. 
 
Secondary Hypotheses 
5 
2.3. 
 
Tertiary Aim 
5 
2.4. 
 
Ancillary Aims 
5 
3.0. 
Background 
6 
3.1. 
 
Cocoa Extract 
6 
3.2. 
 
Multivitamins 
6 
4.0. 
Study Design 
8 
4.1. 
 
Schema 
8 
4.2. 
 
Study Population 
9 
4.2.1. 
 
 
Inclusion Criteria 
9 
4.2.2. 
 
 
Exclusion Criteria 
9 
4.3. 
 
Consent 
9 
4.4. 
 
Intervention 
10 
4.5. 
 
Randomization and Blinding 
11 
5.0. 
Outcomes 
11 
5.1. 
 
Primary Outcomes 
11 
5.2. 
 
Secondary Outcomes 
12 
5.3. 
 
Tertiary Outcomes 
12 
5.4. 
 
Ancillary Outcomes 
12 
6.0. 
Sample Size and Power 
12 
7.0. 
Study Procedures 
13 
7.1. 
 
Recruitment Sources 
13 
7.1.1. 
 
 
Initial Mailings 
14 
7.1.2. 
 
 
Second Mailing 
14 
7.2. 
 
Run-in 
15 
7.3. 
 
Randomization, Dispensing and Blinding 
16 
7.4. 
 
Follow-up 
16 
7.5. 
 
Safety and Adverse Events 
17 

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Abbreviations 
BP: Blood pressure 
BWH: Brigham and Women’s Hospital (Boston, MA), also called “Partners”  
CABG: Coronary Artery Bypass Graft, also called “Coronary Revascularization” 
CCC: Clinical Coordinating Center (WHI; Seattle, WA) 
CHD: Coronary Heart Disease 
COSMOS: COcoa Supplement and Multivitamin Outcomes Study 
CVD: Cardiovascular Disease 
FHCRC: Fred Hutchinson Cancer Research Center (Seattle, WA) 
7.6. 
 
Unblinding 
17 
7.7. 
 
Early Discontinuation 
17 
7.8. 
 
Study Closeout 
18 
7.9. 
 
Data Collection and Management 
18 
7.10. 
 
Outcomes Collection 
18 
7.11. 
 
Documentation and Definition of COSMOS Study Outcomes 
19 
7.11.1. 
 
 
Cardiovascular Disease (CVD) Events 
19 
7.11.2. 
 
 
Cancer 
20 
7.11.3. 
 
 
Deaths 
20 
7.12. 
 
Passive Follow-up 
20 
8.0. 
Biospecimen and Blood Pressure Substudy 
21 
9.0 
Clinic-Based Substudy 
21 
9.1 
Ancillary Studies 
21 
9.2 
COSMOS Cancer Tissue Study 
24 
9.3 
Coronavirus disease (COVID-19) 
24 
10.0. 
Statistical Analyses 
25 
11.0. 
Data Management 
25 
12.0. 
Study Monitoring 
26 
13.0. 
Quality Assurance 
26 
14.0. 
Study Administration and Organization 
27 
15.0. 
Study Timeline 
27 
16.0. 
Ancillary Studies 
28 
17.0. 
Appendix 
28 
18.0. 
References 
30 

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MI: Myocardial Infarction  
NHLBI: National Heart, Lung, and Blood Institute 
VITAL: VITamin D and omegA-3 TriaL  
WHI: Women’s Health Initiative 
Overview 
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 cocoa flavanols , 
including 80 mg (-)-epicatechins) (please see section 4.4 Intervention), and a multivitamin supplement to 
reduce the risk of cardiovascular disease (CVD) and cancer in approximately 13,000 women aged ≥65 years 
and approximately 9,000 men aged ≥60 years with an average of 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.  
The 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 up to 13,000 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 9,000 men among non-randomized respondents of the VITAL who 
expressed interest in research studies and already reported preliminary eligibility information. If necessary to 
reach the enrollment goals, additional men and women who contacted BWH for information about COSMOS 
may be included, along with additional women among non-randomized respondents of the VITAL, plus use of 
targeted mailing lists as needed.  Thus, a total of up to 22,000 women and men will be randomized into the 
COSMOS trial. The study plan involves recruitment over one or more years, including a placebo run-in, and an 
average of 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.  Baseline 
blood and spot urine specimens will be collected from a subcohort of approximately 3,500 women and 3,500 
men participating in COSMOS; blood pressure and anthropometric measurements also will be obtained from 
these participants when possible.  Follow-up measurements will be collected from a subset of the biospecimen 
project participants to assess changes in important nutritional and vascular/metabolic biomarkers related to our 
cocoa flavanol and multivitamin interventions. The design of the trial also allows for the development of 
multiple ancillary studies, including one which will assess the effects of the study agents on cognitive function 
at baseline and follow-up using a web-based application and one which will assess the effects on risk of 
cataract and age-related macular degeneration (AMD).  Additional measurements will be obtained from in-

COSMOS Protocol 
April 1, 2024 
Page 6 
clinic visits at baseline and after 2-years follow-up for approximately 600 COSMOS participants residing in the 
greater Boston area at the Harvard Catalyst Clinical and Translational Science Center.  
(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.) 
2.0. 
Study Objectives 
COSMOS is a randomized, double-blind, placebo-controlled, 2x2 factorial trial of a cocoa extract and a 
multivitamin supplement in up to 22,000 subjects (13,000 women and 9,000 men), including women recruited 
from active, older WHI participants and men and women who expressed interest in research being conducted 
by BWH. The primary objectives of this trial are to evaluate these agents for the maintenance of health. The 
specific hypotheses guiding the design of the trial are as follows:  
2.1. 
Primary Hypotheses: 
1) Cocoa extract (2 capsules/day containing a total of 600 mg/d flavanols, including 80 mg (-)-epicatechin, 
and 50 mg theobromine) (please see section 4.4 Intervention) will reduce the risk of major 
cardiovascular events, defined for these purposes as a composite endpoint of MI, stroke, 
cardiovascular mortality, coronary revascularization, unstable angina or acute coronary syndrome 
(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). 
2.2. 
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 MI, 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, other pertinent nutritional biomarkers, and 
vascular/metabolic biomarkers from baseline to 1, 2, or 3 years of follow-up. 
2.3. 
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.   
2.4    Ancillary Aims: 

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To assess whether the random assignment to daily cocoa extract, compared to placebo, has favorable 
effects on cognitive function over 3 years of follow-up in men and women. 
To assess whether daily cocoa extract and/or multivitamin have favorable effects on the risk of cataract 
and age-related macular degeneration (AMD). 
To assess whether daily cocoa extract and/or multivitamin have favorable effects on the risk of injurious 
fall(s) resulting in healthcare utilization, recurrent falls, physical performance, and fractures. 
To assess whether daily cocoa extract and/or multivitamin have favorable effects on inflammaging and 
epigenetic aging.   
  
3.0. 
Background 
COSMOS is a large-scale randomized trial testing a 
patented, well-studied cocoa extract supplement (Mars 
Symbioscience) and a standard multivitamin (Pfizer Inc) in 
the maintenance of heart health and cancer risk among 
older women and men.  Evidence for the potential benefits 
of these agents for chronic disease risk comes from 
multiple sources. For the cocoa extract intervention, 
randomized trials have demonstrated consistent benefits 
on intermediate outcomes, including blood pressure (BP), 
lipids, insulin sensitivity, and flow-mediated vasodilation, 
but there are no large-scale trials. For multivitamins, a 
large-scale randomized trial in men showed a reduction in 
cancer occurrence which appeared to be concentrated in men with prior cancer diagnoses.1 There are no 
corresponding randomized trial data for women, and the nature of the data in men indicates that replication of 
this finding is needed. For both interventions, a confirmatory large-scale randomized trial could have enormous 
clinical and public health impact.  
The WHI and VITAL study infrastructures provide key resources for COSMOS, eliminating the need for de 
novo recruitment (a major expense of most trials), supporting data collection and cohort follow-up, and 
facilitating adjudication of trial outcomes already collected for all cancer endpoints and CVD endpoints in a 
subcohort of WHI. This approach to recruitment and follow-up is highly innovative and extremely time- and 
cost-efficient. COSMOS also represents an important collaboration among NIH, academia, and industry 
partners donating the cocoa and multivitamin supplements and packaging and  is directly responsive to the 
goal of the April 2013 NHLBI Workshop to facilitate cost-effective clinical trials that leverage existing cohort 
infrastructure such as WHI, and a 2012 Institute of Medicine Workshop on “Large Simple Trials.”  
3.1. 
Cocoa extract 
Cocoa and chocolate are ancient fermented products that the Aztecs made from the bean of the cacao tree, 
Theobroma cacao. Cocoa and chocolate contain catechins and epicatechins, readily water soluble flavonoids 
classified as flavan-3-ols,2 a subclass of flavonoids with vascular health benefits. In the last decade, 
experimental and clinical studies testing the consumption of chocolate (as dark chocolate), cocoa, and high-
dose cocoa flavanols note beneficial effects on antioxidant capacity,3,4 LDL oxidation,5 platelet activation,6,7 
lipid profiles,8,9 endothelium-dependent vasodilation,10,11 inflammation,12,13 blood pressure (BP),14 and glucose 
metabolism, 15 which may translate into important cardiovascular and cancer benefits (Figure 1).  
3.2. 
Multivitamins 
Figure 1. Multiple mechanisms through which cocoa 
products may lower the risk of CVD 
 
Cocoa Products
LDL
Triglycerides
HDL 
Platelet 
adhesion and 
aggregation
Endothelial function
Flow-mediated dilation
Antioxidant capacity
LDL oxidation
Inflammation
Insulin sensitivity 
Glucose metabolism
CVD risk
Blood 
pressure

COSMOS Protocol 
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Page 8 
Multivitamins are the most common dietary supplement, taken by at least one-third of US adults.16,17 
Observational studies of multivitamin use and cancer have had inconsistent findings.18-24 In the recently 
completed Physicians’ Health Study (PHS) II, a randomized, double-blind, placebo-controlled clinical trial 
testing a Centrum Silver multivitamin in 14,641 men aged ≥50 years, we found a modest but significant 8% 
reduction in total cancer,1 and no effect on CVD.25 Notably, in men aged ≥70 years there was a stronger 18% 
reduction in total cancer (P, interaction by age=0.06) and a nonsignificant 9% reduction in CVD (P, interaction 
by age=0.04).1,25 Further, among 1,312 men with a baseline history of cancer in PHS II, we found that daily 
multivitamin use was associated with a significant 27% reduction in total cancer. In addition, there was a 
significant 39% reduction in fatal myocardial infarction (MI) overall. Because the PHS II is the only large-scale 
clinical trial testing a daily multivitamin, these findings require replication to determine whether a multivitamin 
reduces the risk of cancer, particularly among older women and those with a history of cancer. 
The popularity of vitamins, with $23 billion spent annually, the increase in vitamin and mineral fortification of 
foods and beverages, and recent safety concerns over some supplements26,27 all heighten the importance of 
understanding the effects of vitamin supplements. Over half of US adults take vitamins,28-30 with multivitamins 
by far the most common dietary supplement taken. More than one-third of US adults take multivitamins12,13,31 
such as Centrum Silver. The purpose of multivitamins is to reduce nutritional deficiency. Although 
supplementation with high-dose individual vitamins has not reduced cancer risk, multivitamins represent a 
different paradigm of RDA-level supplementation across dozens of vitamins and minerals. Despite the lack of 
clear benefits, US adults still take multivitamin supplements to reduce chronic diseases30 or promote general 
health and well-being.32 In NHANES, less than 25% of supplements taken were recommended by a physician 
or health provider.33 
Cognitive Function 
Dietary interventions have shown that consuming cocoa flavanols can reduce platelet aggregation and improve 
insulin sensitivity, blood pressure and peripheral and central blood flow.34  Given that deleterious changes in 
these markers of health are associated with cognitive decline and dementia, cocoa flavanols may confer 
neuroprotective effects that benefit cognitive function and potentially reduce the risk of neurodegenerative 
disease.  In one human study, daily consumption of cocoa flavanols was associated with improved cognitive 
function (attention, executive function and language) in older men and women with mild cognitive impairment, 
a transitional state between normal cognitive aging and dementia.35  
Eye Health 
The rationale for the COSMOS Eye ancillary study is based on recent findings from the Physicians’ Health 
Study II trial of a beneficial effect of a daily multivitamin in cataract reduction and the plausible benefits of 
cocoa extract in preventing age-related macular degeneration (Protocol #2016P001612: Cataract and AMD in 
a Trial of a Multivitamin and Cocoa Extract). 
Falls and Physical Performance 
Several lines of evidence suggest that flavanols commonly found in cocoa confer beneficial effects on 
muscle function and physical performance. Cocoa is a rich source of water soluble flavanols, specifically 
epicatechins. Results from preclinical and clinical studies have shown promising effects of epicatechins on 
decreasing oxidative stress, improving markers of mitochondrial biogenesis, and increasing grip strength 
and walking speed. Studies in older adults indicate that flavanols have promising effects on 
musculoskeletal physiology and/or physical performance. This ancillary study will test whether 

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supplemental cocoa flavanols prevent falls, slow age-related declines in physical performance, and/or 
reduce fall-related fractures among older persons in the U.S.  
Inflammaging and Epigenetic Aging 
Human aging is characterized by chronic, low-grade inflammation, which has recently been termed 
inflammaging. Inflammaging is exemplified by mild chronic elevation in blood levels of C-reactive protein (CRP) 
and several cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which increase with 
aging. Inflammaging is a highly significant risk for both morbidity and mortality in the elderly. Accelerated 
epigenetic aging that comprises DNA methylation changes has recently emerged as a powerful, novel 
predictor for lifespan and health span, disease susceptibility, morbidity, and mortality risk. DNA methylation is a 
major epigenetic process that regulates gene expression and can be modified by different bioactive 
compounds in foods. This ancillary study will provide insight into the underlying molecular mechanisms for 
cocoa flavanol and multivitamin supplements, and holds great promise for targeting by nutritional interventions. 
 
4.0. 
Study Design 
4.1. 
Schema 
The COSMOS trial will be a randomized, double-
blind, placebo-controlled trial to evaluate the 
benefits and risks of a patented cocoa extract 
supplement (600 mg/d of cocoa flavanols, (please 
see section 4.4 Intervention)) and a daily 
multivitamin (Centrum Silver) in the maintenance of 
heart health and cancer risk among 13,000 women 
aged ≥65 years and 9,000 men aged ≥60 years 
among WHI participants and those contacted but 
not randomized into VITAL, for a total of 22,000 
randomized participants (Figure 2). In order to 
reach the recruitment goals, men and women who contact BWH for information about participating in the 
COSMOS trial may also be included as well as respondents to targeted mass mailings.  This large, simple trial 
represents collaboration between the Division of Preventive Medicine at BWH, Fred Hutchinson Cancer 
Research Center (WHI CCC), WHI Regional Centers, and the WHI Project Office at NHLBI. Each participant 
will be randomly assigned in a 2x2 trial to a cocoa flavanol and/or multivitamin supplement with an average of 
4 years of treatment and follow-up. Follow-up questionnaires at 6 and 12 months and semi-annually thereafter 
will assess compliance, dietary changes, new endpoints, and risk factors. Baseline blood and spot urine 
specimens will be collected from a subcohort of approximately 3,500 women and 3,500 men participating in 
COSMOS; blood pressure and anthropometric measurements also will be obtained from a sample of these 
participants.  Follow-up measurements will be collected to assess changes in important nutritional and 
vascular/metabolic biomarkers related to our cocoa flavanol and multivitamin interventions. Additional 
measurements, including cognitive function, physical function, blood pressure, and other assessments, will be 
obtained from in-clinic visits at baseline and after 2-years follow-up for approximately 600 COSMOS 
participants residing in the greater Boston area at the Harvard Catalyst Clinical and Translational Science 
Center.  The design of the trial also allows for the development of multiple ancillary studies including one which 
will assess the effects of the study agents on cognitive function at baseline and follow-up using a web-based 
Figure 2.  Overview of COSMOS trial of cocoa and multivitamin 
supplements 

COSMOS Protocol 
April 1, 2024 
Page 10 
application.  An ancillary study on eye health will assess the effects of the study agents on risk of cataract and 
AMD. 
The trial builds on existing data collection and outcomes adjudication within the WHI CCC, 4 WHI Regional 
Centers (RCs), the WHI Study Database (WHIX) to facilitate participant tracking and security, and the VITAL 
trial, coordinated at Brigham and Women’s Hospital (BWH) as a recruitment source. Active and placebo 
supplements and packaging will be donated by manufacturers. A detailed medication inventory on all WHI 
participants will also allow us to assess potential modifying effects of regular use of common medications, 
including statins, aspirin, and other medications.  
4.2. 
Study Population  
4.2.1. Inclusion criteria 
1. 
Women will be ≥65 years of age and participating in the current WHI Extension Study. If fewer than 
13,000 women from WHI agree to participate, additional women aged ≥65 years who were contacted 
for but not randomized into VITAL, women who contact BWH to volunteer for the COSMOS trial, and 
those responding to invitations by mail will be eligible.  If the women from VITAL proceeded to the 
stage of the VITAL run-in, they must not have missed >10 days of pill taking per month.   
2. 
Men will be ≥60 years of age who were contacted for but not randomized into the VITAL Trial, men 
who called for information about COSMOS, and those responding to recruitment invitations by mail.   
If the men from VITAL proceeded to the stage of the VITAL run-in, they must not have missed >10 
days of pill taking per month. 
3. 
ResearchMatch.org will be utilized as a recruitment tool for this protocol.  ResearchMatch.org is a 
national electronic, web-based recruitment tool that was created through the Clinical & Translational 
Science Awards Consortium in 2009 and is maintained at Vanderbilt University as an IRB-approved 
data repository (see IRB #090207). 
4. 
Willing to participate, as evidenced by providing informed consent to the BWH and completing all 
required baseline forms. 
 
4.2.2. 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 
randomization unless the participant is willing and able to take the study pills and complete 
questionnaires for the duration of the trial. 
3. 
Current active chemotherapy or radiation treatment for recurrent cancer. 
4. 
Any serious illness that would preclude participation and/or completion of the trial, including the 
diagnosis of kidney failure and current dialysis treatment.   
5. 
Taking cocoa or multivitamin supplements and not willing to forego use during the trial.  
6. 
Taking total supplemental vitamin D >1000 IU/day and not willing to forego use during the trial. 
7. 
Taking total supplemental calcium >1200 mg/day and not willing to forego use during the trial. 
8. 
Extreme sensitivity to caffeine. 
9. 
Consume < 75% of the expected number of both types of supplements during the run-in phase. 
10. Unable to communicate in English due to language barrier or mental incapacity. 
 
4.3. 
Consent 

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Page 11 
The participant’s full understanding of the COSMOS trial is important ethically and for adherence to the 
protocol. Consent forms will be mailed to all individuals who have expressed interest in participating in the 
main COSMOS trial in response to the initial screening survey. All COSMOS subjects are consented by BWH 
and sign the Partners Consent form.  Consent forms for WHI participants will be returned by mail to the WHI 
CCC for data entry. Consent forms for all others will be returned to BWH.  A BWH toll-free telephone number 
will be provided with the corresponding consent form and recipients will be encouraged to call with any 
COSMOS study related questions. A toll-free line for the CCC will also be provided with the corresponding 
consent and recipients will be encouraged to call with any WHI study-related questions. 
The BWH COSMOS consent will permit sharing of all data between the WHI CCC and BWH on the WHI 
participants who consent to COSMOS, including personal identifiers, for the purposes of intervention delivery. 
Similarly, the consent will permit BWH to share COSMOS data with the WHI CCC to facilitate active follow-up 
and passive follow-up through linkage to other sources such as the National Death Index and Medicare.  The 
consent will not allow access to participant PHI by ancillary studies, but will include consent to contact for 
additional studies. 
COSMOS participants who agree to provide blood samples, urine samples, blood pressure, and 
anthropometric measurements will sign a separate consent form specifically related to the biomarker project.   
COSMOS participants in clinic-based visits at the Harvard Catalyst Clinical and Translational Science Center 
will also be required to sign a separate consent form that is included under a separate study protocol that 
specifically relates to the clinic-based COSMOS study project. 
Separate study protocols and/or consent forms will be developed as appropriate for all ancillary studies to 
COSMOS, including a project for web-based cognitive function assessments for approximately 4,000 
participants at baseline and follow-up. 
The BWH COSMOS consent forms conform to all Human Subjects Protections as outlined by the US 
Department of Health and Human Services (DHHS) Office for Human Research Protections (OHRP) and 
guided by the Institutional Review Offices (IROs) of the participating institutions. The consent will be reviewed 
by each participating institution’s (BWH, FHCRC) Institutional Review Boards (IRB).  
4.4. 
Intervention  
Cocoa Extract supplements:   Active cocoa extract (600 mg/d of cocoa flavanols) and matching inert placebo 
with no cocoa flavanols will be provided by Mars Symbioscience.  Participants will be asked to take two 
capsules per day, totaling 600 mg/d.  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.   
Multivitamin supplements:  Active multivitamin (marketed as Centrum Silver™) and matching inert placebo will 
be provided by Pfizer Inc. Participants will take one tablet per day.  

COSMOS Protocol 
April 1, 2024 
Page 12 
The manufacturers will perform quality control testing to ensure their products contain the correct amounts and 
are free of contaminants.  
Study supplements will be packaged in calendar packs provided by Contract Pharmacal Corp (CPC) to 
promote adherence to daily dosing and facilitate self-reports of adherence to pill-taking. Participants will be 
instructed to take their study supplements at the same time each day.   
4.5. 
Randomization and blinding 
Eligible participants will be randomized into one of 4 treatment arms in equal proportions:  
Active Multivitamin and Active Cocoa Extract;  
Active Multivitamin and Placebo Cocoa Extract;  
Placebo Multivitamin and Active Cocoa Extract;  
Placebo Multivitamin and Placebo Cocoa Extract.   
The algorithm will use a randomized permuted block approach, stratified by (at minimum) sex, age group, and 
recruitment center (WHI or BWH). The date of randomized treatment assignment will be considered the formal 
enrollment date.   
Whenever possible, household partners (e.g., spouse/partner) of a randomized COSMOS participant will be 
assigned to the same treatment group, as the corresponding randomized participant.  To ensure balance within 
strata at the participant-level, the household partner will occupy the next available allocation with the same 
treatment, as the randomized participant. The strata of the household partner will be determined by the 
household partner’s individual characteristics, and not the characteristics of the corresponding randomized 
participant. 
BWH will receive all calendar packs for distribution to COSMOS participants and maintain blinding to treatment 
assignments.  
5.0. 
Outcomes 
Primary and secondary outcomes will be ascertained initially through self-report, proxy-report, or death 
certificate, and confirmed through medical record review using definitions and procedures established in the 
WHI.  For COSMOS participants recruited from WHI, all cancer events and ~25% of CVD events in WHI will be 
adjudicated through currently funded ongoing WHI procedures. The remaining CVD events among WHI 
participants and all cancer and CVD events in the remaining participants will be documented and adjudicated 
using identical definitions and procedures by WHI physician adjudicators and COSMOS staff at BWH who are 
blinded to randomization assignment.   
5.1. 
Primary Outcomes 
Cocoa Extract:  Centrally adjudicated major 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;  
Multivitamin:  Invasive cancers of any site other than non-melanoma skin cancer as confirmed by medical 
record review and coded according to SEER standards. 

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Page 13 
 
5.2. 
 Secondary Outcomes 
Cocoa Extract: Composite endpoint of MI, stroke, cardiovascular mortality, and coronary revascularization; 
Invasive cancers of any site other than non-melanoma skin cancer as confirmed by medical record review and 
coded according to SEER standards. 
Multivitamin: Centrally adjudicated major 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.   
Cocoa extract and a daily multivitamin: 
Major cardiovascular events (the combined endpoint of composite endpoint of MI, stroke, cardiovascular 
mortality, coronary revascularization, unstable angina or ACS requiring hospitalization, carotid artery surgery, 
and peripheral artery surgery or angioplasty) plus all-cause mortality; 
Individual cardiovascular events, including MI, stroke, cardiovascular mortality, coronary revascularization, 
unstable angina or ACS requiring hospitalization, carotid artery surgery, peripheral artery surgery or 
angioplasty, and total mortality; plus site-specific cancers, including breast, colorectal, and lung cancer; 
Invasive cancer in participants with a history of cancer at COSMOS baseline. 
5.3. 
Tertiary Outcomes 
Cocoa extract and/or a daily multivitamin: Synergistic effects on risk of major cardiovascular events or cancer, 
and if the effects vary by nutritional status or medication use.   
5.4. 
Ancillary Outcomes 
COSMOS Mind – Cocoa extract and/or a daily multivitamin: Telephone-based assessments of global cognitive 
function, executive function, and memory. 
COSMOS Web – Cocoa extract: Internet-based neuropsychological testing battery, including the ModBent test 
(cognitive test of novel object recognition), the Spatial Learning Task, and the Flanker Task (cognitive test of 
attention, inhibition, and executive control). 
COSMOS Eye – Cocoa extract and/or a daily multivitamin:  cataracts, cataract surgery, and age-related 
macular degeneration (AMD). 
COSMOS Falls and Physical Performance – Cocoa extract and/or a daily multivitamin: Injurious fall(s) resulting 
in healthcare utilization (visit to a healthcare provider or hospital); recurrent falls; physical performance as 
assessed by grip strength (by dynometer), walking speed (6 meters); and the Short Physical Performance 
Battery including tests of standing balance, walking speed, and chair stands; incident total, spine, 
forearm/wrist, and hip fractures; and bone density changes. 
COSMOS Inflammaging and Epigenetic Aging – Cocoa extract and/or a daily multivitamin: epigenetic aging; 
inflammaging; and effects on inflammaging are mediated by epigenetic aging, and the impact on CVD risk.  
6.0.  
Sample size and power   

COSMOS Protocol 
April 1, 2024 
Page 14 
Power calculations for the primary endpoints of major cardiovascular events and total invasive cancer are 
based upon a 2x2 factorial trial in approximately 22,000 participants, including 13,000 women aged ≥65 years 
and 9,000 men aged ≥60 years. Based on the log-rank test (equivalent to score tests for hazard ratios from a 
Cox model without covariates), Freedman36 has shown that the power, 1-β, of this test to detect a specified 
hazard ratio HR based on a two-sided test with significance level α is a simple function of the number of 
accrued events, m, in the two groups combined: 1-β = Φ(√m (|HR-1|)/(|HR+1|) - z1-α/2), where Φ is the standard 
normal cumulative distribution function.  The factorial design of this trial is motivated primarily by efficiency.  
The scientific justification for testing each intervention is independent of the other and stands alone. Therefore 
each comparison (multivitamins versus placebo and cocoa extract versus placebo) will be based on a marginal 
test (but controlling for the other intervention) at a level of α =0.05.   
Estimates of study power and the expected numbers of confirmed, accrued events in Table 1 are based on the 
following assumptions: (1) independent and equal allocation of participants to each treatment; (2) an age 
distribution based on that observed among WHI women ≥65 years and men aged ≥60 years responding to the  
VITAL mailings; (3) annualized age-specific event rates based on observed rates during WHI and VITAL 
follow-up, adjusted for aging; (4) same event rates for men and women given that women are approximately 5 
years older than men; (5) mean trial follow-up of 4 years, with nominal loss to follow-up as seen previously in 
WHI, VITAL, and mail-based trials by the BWH Division of Preventive Medicine; and (6) an average of 80% 
compliance.  These assumptions remain the same as proposed for our original power calculations for 18,000 
participants. 
With approximately 22,000 
randomized participants, there will 
be at least 80% power to detect a 
11% relative hazard reduction in 
total CVD, and >95% power to 
detect such a reduction in the 
important composite of total CVD 
plus all-cause mortality with the 
expected number of events. 
Similarly, there would be at least 
90% power to detect a 14% 
reduction in total cancer. Power for 
key secondary outcomes are highly 
dependent on the frequency of the 
events.  
7.0. 
Study Procedures  
7.1. 
Recruitment Sources 
COSMOS participants will be recruited from three primary sources, the current WHI Extension Study 
participants, individuals who have responded to recruitment activities for VITAL but who were not randomized, 
and targeted mailings.  The initial recruitment and screening of potential COSMOS participants will be 
conducted separately, by the CCC for WHI participants and by BWH for VITAL respondents . If necessary to 
meet recruitment goals, additional men and women who called for information about the COSMOS or respond 
to mass mailings will be recruited by BWH.  ResearchMatch.org, a national electronic, web-based recruitment 
Table 1.  Power for effects of a single agent on specified endpoints in a factorial trial of 
22,000 women and men, with 4 years of treatment and follow-up (#s in 
parentheses are expected number of events in both groups combined) 
Observed 
RR * 
True 
RR † 
Total 
CVD 
Total 
CVD + 
Mortality 
Total 
Cancer 
CVD 
death 
Stroke 
MI 
Breast 
cancer 
Placebo event rate 
(per 100 p-y) 
3.0 
5.0 
2.2 
1.0 
0.9 
0.8 
0.8 
0.90 
0.875 
76% 
(2479) 
93% 
(4106) 
63% 
(1837) 
-  
(824) 
- 
  (743) 
-  
(661) 
-  
(661) 
0.85 
0.812 
98% 
(2416) 
>99% 
(4005) 
93% 
(1790) 
64% 
(803) 
59% 
(723) 
54% 
(644) 
54% 
  (644) 
0.80 
0.750 
>99% 
(2353) 
>99% 
(3903)  
>99% 
(1743) 
88% 
(781) 
84% 
(704) 
80% 
(627) 
80% 
(627) 
0.75 
0.687 
>99% 
(2290) 
>99% 
(3801) 
>99% 
(1695) 
98% 
(760) 
96% 
(685) 
94% 
(609) 
94% 
(609) 
0.70 
0.625 
>99% 
(2226) 
>99% 
(3697) 
>99% 
(1648) 
>99% 
(738) 
>99% 
(665) 
99% 
(592) 
99% 
(592) 
0.65 
0.560 
>99% 
(2162) 
>99% 
(3592) 
>99% 
(1600) 
>99% 
(717) 
>99% 
(646) 
>99% 
(575) 
>99% 
(575) 
*  Observed RR = intent-to-treat RR, including noncompliant participants and 80% compliance.  
 
† True RR = that with perfect compliance. 
-   Power < 50% 

COSMOS Protocol 
April 1, 2024 
Page 15 
tool created through the Clinical & Translational Science Awards Consortium in 2009 and maintained by 
Vanderbilt University as an IRB-approved data repository (see IRB #090207), will be utilized to help meet 
targeted recruitment goals. 
7.1.1. Initial Mailings 
WHI Participants:  The CCC will establish pre-eligibility of WHI participants from the most recently available 
database of all WHI questionnaires and outcomes data (expected yield of 77,011). The CCC will mail each 
identified WHI participant a recruitment packet containing a letter and information explaining the rationale for 
the COSMOS trial and what participation would entail, a brief eligibility and interest questionnaire and a 
prepaid return envelope. The questionnaire will collect information on eligibility and demographics. Women 
who do not respond to the first mailing will be sent a repeat mailing within 8 weeks.    
The CCC will scan the returned packets from WHI participants into the central COSMOS database maintained 
at the CCC and a computer program will evaluate the responses on the enrollment questionnaire along with 
the WHI questionnaire to classify respondents as ineligible, pending eligible, or eligible.  
VITAL respondents:   
Men in the COSMOS trial will be recruited from those contacted for the VITAL trial. BWH will identify men who 
were contacted for VITAL, but not randomized and are eligible for COSMOS based on all available data.  BWH 
will also recruit men who called to request information about the trial and those who respond to targeted mass 
mailings. 
Responses will be returned to BWH. BWH staff will scan the documents into the central COSMOS database 
and a computer program will evaluate the responses on the enrollment questionnaires to classify the 
respondents as ineligible, pending eligible, or eligible. For pending eligibles, BWH will either call the potential 
participant or mail a brief follow-up form to clarify incomplete or inconsistent responses.   
If needed to meet enrollment goals, women who responded to the VITAL recruitment process, those who 
called for information about the trial, and those who respond to the targeted mass mailings will be recruited into 
COSMOS following the same protocol as for men, but limited to women ≥65 years of age.  
Respondents who were willing but not eligible to participate will be sent a brief thank you note after all phases 
of screening have been completed.  The CCC will mail for WHI participants and BWH will mail for non-WHI 
participants. 
Additional men and women who are interested in joining the trial will be given the option of completing 
questionnaires online. The data will be collected and managed using REDCap (Research Electronic Data 
Capture), a secure, HIPAA-compliant web-based application hosted by Partners HealthCare Research 
Computing Enterprise Research Infrastructure & Services (ERIS). These potential participants will be directed 
to the study website where they will find a link to a REDCap survey that will allow them to submit their name, 
gender, and contact information. At that time, they will also have the option of completing the COSMOS 1 
screening questionnaire through REDCap. 
7.1.2. Second Mailing   
Each site (CCC and BWH) will send a second mailing to those potential COSMOS participants who remain 
willing and eligible for the trial after the initial mailing. This packet will contain an expanded cover letter; BWH 
COSMOS trial consent form; an additional baseline questionnaire with questions on eligibility; demographic, 

COSMOS Protocol 
April 1, 2024 
Page 16 
lifestyle, and clinical risk factors; dietary factors; and a return envelope. The Fred Hutchinson Cancer Research 
Center (WHI CCC) sends recruitment mailings and the Partners consent form to women they previously 
enrolled into the WHI.   
Participants with any questions before they sign and return their BWH COSMOS informed consent will all be 
offered the opportunity to call a BWH toll free number and speak with COSMOS research staff or key 
Investigators as needed. Responses will be returned to the originating sites for evaluation of eligibility.  Non-
respondents will be sent a repeat mailing within a few months. Those with uncertain eligibility will be contacted 
by mail or phone to resolve any issues. 
Respondents who are willing but not eligible will be sent a brief thank you note after all phases of screening 
have been completed. The CCC will mail for WHI participants and BWH will mail for non-WHI participants. 
7.2. 
Run-in 
Potential participants who remain eligible and interested after the second mailing will be asked to complete at 
least a 2-month placebo run-in (optimally 3-4 months) to eliminate poor compliers prior to randomization and 
increase study power.37  The participants will not be told that the pills they are provided are placebo.  
BWH will send up to a 6-month supply of multivitamin placebo tablets and cocoa extract placebo capsules to 
all respondents to the second mailing who remain eligible and who provided a signed consent form. The 
additional supply will allow daily pill taking to continue uninterrupted before randomization. Cocoa placebo 
capsules and multivitamin placebo tablets will be packaged in calendar packs, and dispensation will be tracked 
using lot numbers and tracking systems in place at BWH. Participants will be asked to take three pills (two 
cocoa placebo and one multivitamin placebo) per day.  
During the placebo run-in, we will send a food frequency questionnaire (FFQ) to all participants that includes 
questions on dietary sources of cocoa flavanols, the use of nutritional supplements (including multivitamins), 
and other foods. 
Also during the run-in, participants who are willing to provide blood samples will be sent information and 
materials inviting them to provide study data.  Those who are willing and eligible for the Boston area clinic-
based visits will be sent an invitational mailing with information concerning the opportunity to participate in this 
portion of the COSMOS trial.  Participants who express interest in any ancillary projects such as the web-
based, cognitive function sub-study, will receive separate mailings with detailed information concerning the 
projects and informed that their participation is optional to the main trial.  
We will partner with Wake Forest (COSMOS Mind) and Columbia University (COSMOS Web) to enroll 
participants in these sub-studies. Once the participants enter the run-in, those who meet the requirements  for 
these 2 sub-studies will be contacted by letter to opt-in in either substudy. If the participant returns the letter 
requesting participation in 1) COSMOS Mind, we will grant Wake Forest access to contact the participants and 
complete the phone interview. BWH will develop a data sharing agreement with Wake Forest to allow for these 
cognitive data to be analyzed, and Wake Forest has separate IRB approval for these COSMOS Mind activities. 
If the participant returns the letter requesting participation in 2) COSMOS Web, we will send the participants a 
letter or email with instructions on how to access and complete the web-based test. BWH will receive the web-
based data, and will develop a data sharing agreement with Columbia University to allow for these cognitive 
data to be analyzed. Participants who complete a baseline test for COSMOS Mind (goal of 2,200) and 
COSMOS Web (goal of 4,000) will be contacted again at years 1, 2, and 3.  

COSMOS Protocol 
April 1, 2024 
Page 17 
After at least 8 weeks from the start of the run-in, the CCC will mail WHI participants, and the BWH to non –
WHI participants, a follow-up adherence and safety questionnaire asking about continued eligibility, willingness 
to participate in the trial, pill compliance, potential side effects, and other relevant lifestyle and clinical risk 
factors. Non-responders or those with uncertain eligibility will be contacted by mail or phone to resolve any 
issues. Responses will be scanned into the database and final eligibility will be determined. Those who are 
willing but not eligible will be sent a brief thank you note after all phases of screening have been completed 
from the CCC for WHI participants, and from BWH for non-WHI participants. 
7.3. Randomization, Dispensing and Blinding 
The WHI CCC will be responsible for randomizations and BWH will be responsible for dispensing study 
supplements.  Once all eligibility data are collected and recorded in the central database, the WHI CCC will run 
a computerized function in the COSMOS database that will confirm all items of eligibility and if appropriate, 
allocate eligible participants into one of the 4 intervention groups. Once the randomization is done, BWH staff 
will receive notification of the participant ID to dispense.  BWH will mail a supply of the appropriate 
supplements to the participant. All supplements will be labeled with unique lot numbers for tracking purposes 
and will not indicate whether the contents are active or placebo to assure blinding of all participants and staff 
involved in participant contact and outcomes ascertainment and adjudication.   
WHI participants are assigned to one of 4 WHI Regional Centers or one of 5 affiliated subsites or the CCC for 
selected follow-up and outcomes documentation responsibilities.  These 4 Regional Center sites (RCs) are: 
University at Buffalo (Jean Wactawski-Wende, PI), Wake Forest University (Sally Shumaker, PI), Ohio State 
University (Rebecca Jackson, PI), and Stanford University (Marcia Stefanick, PI). The 5 affiliated subsites 
include Brigham and Women’s Hospital (JoAnn Manson, PI), University of Pittsburgh (Lewis Kuller, PI), 
University of Florida (Marian Limacher, PI), Iowa State University (Jennifer Robinson, PI) and the University of 
Arizona (Cynthia Thompson, PI).   For COSMOS, all participants recruited from the list of VITAL responders 
and others recruited by BWH will be assigned to BWH for the purposes of these follow-up related activities.    
7.4. 
Follow-up 
Approximately 6 months and 12 months following randomization and semi-annually thereafter, COSMOS 
participants will be mailed a follow-up packet containing a cover letter, scannable follow-up questionnaires, and 
a return envelope.  Questionnaires will assess compliance with randomized treatments, use of non-trial cocoa 
and/or multivitamins, dietary intake of chocolate, cocoa, and related foods, risk factors, and update medical 
history.  Participants who do not respond to the follow-up mailing within 8 weeks will be sent a second mailing.  
Those who do not respond to the second mailing within 8 weeks will be contacted by phone.  COSMOS 
participants who are in the WHI will receive separate annual mailings from the WHI CCC that include the WHI 
Form 33-Medical History update and a WHI medical records.   
Up until the 12-month post-randomization follow-up phase, follow-up packets will be returned to the CCC from 
participants recruited by WHI and to BWH for participants recruited by BWH for scanning into the COSMOS 
database. Starting with the 12-month questionnaires, all COSMOS-specific questionnaires will be returned to 
the BWH for scanning into the database and follow-up.  Packets will be reviewed to determine whether there 
are any notes from participants requiring attention. Then data collection forms will be scanned and imaged and 
those indicating there are safety concerns will be immediately flagged for follow-up by BWH staff.  Forms that 
indicate a study outcome may have occurred will be evaluated and processed according to existing WHI 
procedures. For WHI participants, Regional Centers will receive reports of all potential outcomes that require 
documentation as well as the contact information for the health care-provider associated with that outcome. 

COSMOS Protocol 
April 1, 2024 
Page 18 
For BWH participants, reports of study outcomes will be evaluated by BWH staff in accordance with existing 
WHI guidelines.   
BWH will resupply each participant with their blinded calendar packs of assigned supplements at 
approximately 12 months post-randomization and annually thereafter. The timing of these mailings will be 
determined to reduce the likelihood of interruptions in use without considerable overlap.   
At 6-month intervals between annual questionnaires, all participants will receive an interim questionnaire to 
address compliance, potential side effects related to the interventions, and collect records to confirm key 
endpoints. COSMOS participants will also be given the option of completing annual and interim follow-up 
questionnaires online through an e-mailed link. The online data will be collected and managed using REDCap 
(Research Electronic Data Capture), a secure, HIPAA-compliant web-based application hosted by Partners 
HealthCare Research Computing Enterprise Research Infrastructure & Services (ERIS). WHI participants 
already get a newsletter for the purposes of maintaining contact information at 6 month intervals; all COSMOS 
participants will receive annual newsletters to maintain contact as well.   
 7.5. 
Safety and Adverse Events  
The interventions used are generally considered to be safe; indeed multivitamin use is ubiquitous so few if any 
serious adverse effects attributable to use of these supplements are expected. Participants will be fully 
informed of the known risks and benefits and participants will be provided with a toll-free number to call at any 
time if they have concerns about potential adverse effects of these interventions.  In addition, routine data 
collection will assess participant experience with a range of potential conditions that may be affected. Study 
staff will follow standardized IRB and Human Subjects guidelines for determining whether the event is an 
adverse event (AE), serious adverse event (SAE), or unanticipated problem (UP) and follow national and 
institutional reporting requirements. These reports may come to either BWH or the CCC.  If the report comes 
initially to the CCC, it will be referred to BWH within 24 hours for evaluation.  BWH staff will determine whether 
the participant should continue with the COSMOS intervention or stop, either permanently or temporarily.  
Regardless of intervention status (continue, stop, stop temporarily), participants will be followed for study 
outcomes.  For cocoa extract, potential side effects include gastrointestinal tract symptoms (constipation, 
diarrhea, dyspepsia, gastritis, and nausea). For multivitamins, fatigue, drowsiness, skin rash or discoloration, 
migraine, and minor bleeding (hematuria, epistaxis, easy bruising/other bleeding) will be considered potential 
side effects. We will also consider other potential side effects as appropriate. 
Blood drawing may cause a small amount of pain.  In addition, there may be a temporary bruise or “black and 
blue mark.”  Rarely, people faint when their blood is drawn.  Very rarely, the vein may become red and swollen, 
or infected.   
BWHI staff will be responsible for all regulatory reporting.  
7.6. 
Unblinding   
If in the judgment of the BWH staff reviewing the status of a participant reporting a safety concern, the 
participant and/or her/his health care provider needs to be informed of the supplements they were using, an 
authorized unblinding officer in the BWH staff will log into the COSMOS database and execute a database 
function that will provide the treatment assignment. The unblinding officer will be required to record the reason 
for unblinding, and the staff member who requested it, if she or he is not the unblinding officer directly. 
7.7. 
Early Discontinuation 

COSMOS Protocol 
April 1, 2024 
Page 19 
Participants in COSMOS will be allowed to change the nature of their participation at any time. Those who wish 
to discontinue one of the supplements will be allowed to continue all other aspects of the protocol. Similarly 
those who are not willing to take any of the supplements but are willing to provide other follow-up information 
will continue to receive all follow-up mailings but will not be dispensed supplements.  For WHI participants, 
withdrawal from COSMOS will not affect their participation in the WHI Extension Study. 
7.8. 
Study Close-out 
To assure complete ascertainment of outcomes, a final data collection packet containing a cover letter and a 
final COSMOS follow-up questionnaire will be sent to each participant at the end of their intervention period.  
COSMOS participants who are in WHI will also receive the WHI Form 33 Medical History Update and a 
medical release.  Participants will not be unblinded without cause until the final Form 33 has been collected to 
assure unbiased outcomes data collection.  Participants will be sent their unblinded treatment assignment and 
a brief lay-version of the primary study results when available. 
7.9. 
Data Collection and Management 
All trial self-reported information will be obtained directly from COSMOS participants or their designated 
proxies through the baseline, interim, and follow-up postcards and questionnaires. COSMOS participants 
recruited by the WHI will be followed by the WHI CCC prior to the 12-month post-randomization phase.  
Beginning with the 12-month follow-up phase, all participants will be followed by BWH staff.   
The WHI CCC study documents mailed from and returned to the WHI CCC will use mark sense technology 
(bubble forms) consistent with the 20 year history of WHI participant data collection forms.  The CCC will 
review, mark comments, and scan all the questionnaires using Scantron forms and imaging so that the image 
of the form will be accessible to WHI staff.  The CCC will key enter the consent forms of WHI participants and 
store images of all forms electronically.  
BWH questionnaires will be optically scanned and the data extracted into the computer.  The relevant software, 
Cardiff TeleForm, has been successfully used at BWH for several years in the WHS, PHS, and VITAL trials.  
Inconsistent and unclear data will be reviewed by BWH staff who will edit misread variables.  All data will 
undergo additional within-form and across-time checks to verify accuracy.  The BWH database will be backed 
up nightly, ensuring at least two current copies maintained at BWH at all times.   
The BWH computing system, which was fine-tuned in previous trials conducted by the BWH Division of 
Preventive Medicine, will track each participant’s stage in the study and level of participation.  Letters, 
questionnaires, and follow-up reminders will be automatically generated.  Names, addresses, telephone 
numbers, participant status, and processing information will be kept up to date and data from questionnaires, 
letters, and phone calls will be entered directly into the database.  When talking to study participants, study 
personnel will have ready access to identifying information, participation level, and content of previous study-
related telephone calls.   
Nightly transfers of study data between the WHI CCC and BWH will ensure the availability of the most current 
participant information for both study sites.  COSMOS participant data is available only to authorized staff 
members at both BWH and the WHI CCC.    
7.10.  Outcomes Collection 

COSMOS Protocol 
April 1, 2024 
Page 20 
For efficiency and to maintain consistency with previous work in WHI, all COSMOS outcomes processing will 
use the existing WHI procedures to ascertain and validate outcomes of interest for WHI and non-WHI 
participants. The CCC will send the Form 33--Medical History Update and a standardized medical release form 
as part of their follow-up packet to ascertain self-reported outcomes of interest to all female COSMOS 
participants from the WHI.  CCC staff will scan these returned forms into the WHI database.   
COSMOS participants who are part of the WHI Medical Records Cohort (MRC) will have medical records 
retrieval and adjudication performed per normal WHI procedures. COSMOS participants who are part of the 
WHI Self-Report Cohort (SRC) will be flagged in the database and will enter the records retrieval and 
adjudication process exactly as the MRC participants. The flagging will be used to segregate these cases from 
the self-report cohort for billing purposes.   
All potential COSMOS outcomes among WHI participants will be flagged and identified in the appropriate 
Regional Center reports.  Regional Centers will review questionnaires for completeness and for events 
requiring medical records. The Regional Centers will contact these COSMOS participants as needed to clarify 
or complete responses and confirm the participant signed the Release of Information form on the Medical 
History Update questionnaire. If not, or if an institution-specific medical release form is needed, Regional 
Center staff will obtain the necessary release form.  Regional Centers will then obtain the required medical 
records and submit them to the CCC electronically following existing WHI procedures. Returned documents 
will be reviewed by CCC staff.  For CVD outcomes that fall within the scope of the WHI adjudication plan, the 
CCC will send the associated medical records to WHI physician adjudicators for review and confirmation (or 
denial) of outcomes.  
COSMOS participants recruited from BWH who report any of the COSMOS outcomes will be sent a medical 
release form by BWH staff and will enter a records retrieval and adjudication process similar to the WHI at 
BWH.  CVD outcomes will be sent to BWH adjudicators who are familiar with WHI outcomes definitions and 
procedures. BWH adjudicators will use an online adjudication system to adjudicate these events according to 
existing WHI definitions.   
Since unstable angina and ACS requiring hospitalization are not adjudicated for WHI participants in COSMOS, 
all of these self-reports will be adjudicated by BWH staff using the existing medical release document, record 
retrieval, and adjudication procedures used by BWH for all other outcomes. 
All cancers for WHI participants will be reviewed and coded according to SEER standards by trained cancer 
coders at the CCC.  BWH staff will provide equivalent coding to cancers for COSMOS participants who are not 
also part of WHI.  
All outcomes adjudicators and cancer coders will be blinded to individual randomization assignment and all 
interim treatment arm contrasts for all study outcomes.  
7.11. Documentation and Definition of COSMOS study outcomes 
7.11.1. Cardiovascular Disease (CVD) events:  For CVD events, discharge summaries, ECGs, laboratory 
values, and test reports will be sought.  
Definite and probable nonfatal MI requiring overnight hospitalization is defined with an algorithm based on 
standardized criteria including cardiac pain, cardiac enzymes and troponin levels, and ECG findings. MI during 
surgery or aborted by thrombolytic therapy or procedures are also included.  

COSMOS Protocol 
April 1, 2024 
Page 21 
Coronary heart disease (CHD) death includes deaths consistent with CHD as an underlying cause.  
Coronary revascularization includes documented coronary artery bypass graft (CABG) surgery, percutaneous 
transluminal coronary angioplasty (PTCA), coronary stent, or artherectomy.38  
Unstable angina or ACS requiring hospitalization includes review of medical records for reports of increased 
pain, use of medications to alleviate pain, and evidence of troponin leak, as well as other related factors. 
Carotid artery surgery and peripheral artery surgery documentation includes review of surgical and radiology 
reports.  
Stroke is classified according to the Trial of Org 10172 in Acute Stroke Therapy (TOAST)39 and Oxfordshire 
subtype.40 Supporting the confirmation of major CVD events by medical record review through the COSMOS 
would be of tremendous value to the WHI cohort. 
7.11.2. Cancer:  For incident cancers, discharge summaries, pathology reports, operative reports, and 
diagnostic or treatment procedure reports, including both inpatient and outpatient diagnoses will be requested.  
Invasive cancer is considered confirmed if a pathology report substantiates a malignant primary invasive 
cancer at any location other than non-melanoma skin cancer.38 All histologic types and anatomic subsites are 
included. Noncancerous colorectal polyps, atypical benign breast disease and other premalignant benign 
conditions are not included. Second primaries at a site and recurrences of cancer will be ascertained. 
Tissue samples will be collected from COSMOS participants with confirmed diagnoses of incident cancer.  
(Please see section 9.2 regarding the proposed COSMOS Cancer Tissue Study.) 
7.11.3. Deaths:  For participants determined to be deceased, BWH or WHI Regional Center staff, as 
appropriate, will retrieve a death certificate. A condolence letter will be mailed to the family, requesting 
permission to obtain medical records and a copy of the death certificate.  If the family does not provide the 
death certificate, a copy will be requested from the state vital records bureau where the participant died.  
If there is indication on the death certificate of a COSMOS outcome of interest, a case will be opened, and 
medical records pursued to confirm (or deny) the outcome. 
7.12. Passive follow-up. 
The CCC periodically conducts a linkage to the National Death Index data base to ascertain vital status and 
cause of death information for all WHI participants who have been lost to follow-up or for known deaths for 
cases where we could not obtain records.  The CCC will expand this search to include all COSMOS 
participants including a final search at the end of the COSMOS follow-up.  
To complement the standardized methods for endpoint validation in COSMOS, we will use Centers for 
Medicare & Medicaid Services (CMS) database linkage. We will obtain annual updates of information on all 
inpatient and outpatient claims as well as durable medical equipment and we anticipate access to the 
prescription drug databased shortly. This database includes US adults aged ≥65 years, matching the entire 
WHI population and the majority of men and women recruited by BWH for whom we also expect high 
coverage. Linkage to other national databases, for example cancer registries or the Health Maintenance 
Organization Research Network, may also be done to improve the efficiency or the comprehensiveness of 
outcomes collection.  

COSMOS Protocol 
April 1, 2024 
Page 22 
8.0.  
Biospecimen and Blood Pressure (BP) Substudy  
To determine whether cocoa flavanols and/or a daily multivitamin use will significantly change levels of blood 
flavonoids, other pertinent nutritional biomarkers, vascular/metabolic biomarkers, and blood pressure from 
baseline, we will conduct a substudy in a sample of approximately 3,500 male and 3,500 female COSMOS 
participants who sign a separate consent for this additional procedure at baseline. COSMOS participants 
selected will either have baseline bloods and urine collected on their own through mailed blood kits that are 
returned by the participant, or have bloods, urine, BP, and brief anthropometric measurements collected and 
shipped through Examination Management Services, Inc (EMSI). As an alternative to EMSI, Quest diagnostic 
labs are available to assist with the specimen collections and shipments. A subgroup of these participants will 
also have follow-up samples and measurements collected again during follow-up using similar procedures.  
The total amount of blood collected will be 80 ml: 40 ml at baseline and 40 ml at follow-up. The total amount of 
urine collected will be 20ml: 10ml at baseline and 10ml at follow-up.  
BWH will manage this protocol at baseline and post-randomization time points. BWH will be responsible for 
consenting participants and tracking, storing, and distributing COSMOS bloods and urine to appropriate 
laboratories. For assays related to COSMOS, BWH will coordinate with the labs for shipping, testing protocols 
and receipt of results data. One half of the specimen vials from WHI participants which are not used for the 
COSMOS study will be shipped to the WHI repository for storage at the conclusion of the COSMOS trial. 
These specimens will be inventoried and tracked in the WHI Study Tracking System (WHIST). Should the 
COSMOS blood collected for the parent trial fail to yield adequate lab results, BWH may request the CCC to 
ship a replacement vial for retesting. 
9.0. 
Clinic-Based Sub-study 
Additional measurements will be obtained from clinic-based visits at baseline and after 2-years follow-up for 
approximately 600 COSMOS participants residing in the greater Boston area at the Harvard Catalyst Clinical 
and Translational Science Center (CTSC). An equal number of women and men will be recruited.  The clinic-
based visits will include cognitive function assessments, physical assessments, blood pressure, and other 
measurements.  A separate protocol and consent form will be developed and approved by the BWH IRB for 
the clinic-based COSMOS study visits. 
9.1. Ancillary Studies 
COSMOS Mind 
COSMOS Mind cognitive data collection protocol will be modeled after the ongoing WHIMS-ECH and WHIMS-
Y telephone-based protocols.  Each assessment will be conducted by trained and certified examiners from the 
COSMOS-Mind Coordinating Center at Wake Forest and will be electronically audio-recorded for quality 
assurance.  The interview consists of Story Recall 1 & II, Oral Trail Making test, Verbal Fluency, Number Span 
Test, Digit Ordering Test, Cognitive Change Index, Geriatric Depression Scale-Short Form and the Women’s 
Health Initiative Insomnia Rating Scale. The interview will take approximately 45 minutes to complete.  
Participants’ Responses will first be recorded on paper versions of the test and later entered into a dedicated 
and secure data management website.  A secure web-based call tracking system will be used to monitor 
participant contact information. Data will be managed from a secure ftp site at Wake Forest. The interview 
takes approximately 45 minutes. 
COSMOS Web 

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COSMOS Web was designed as a ‘novel object recognition’ task. During the immediate matching trials, 
participants view a single complex stimulus for 10 seconds; following a 1 second delay they are asked to select 
which one of two objects is identical to the studied stimulus.  Following all matching trials, participants are 
shown serially individual complex objects and asked to indicate whether each object is identical to any of the 
target stimuli studied during the immediate matching trials.  On these recognition trials, half the stimuli are 
targets and half are foils.  The primary dependent variable for the COSMOS Web is the mean reaction time 
(ms) for correct rejections of foil stimuli on the delayed recognition trials.  Multiple versions (alternate forms) 
were created for repeat administration.  There are 2 other cognitive assessments, Spatial Learning task and 
Flanker Task, in the web-based assessment.  The interview takes approximately 25 minutes to complete. 
COSMOS Eye 
COSMOS Eye endpoints will be identified from reports on baseline and annual follow-up COSMOS 
questionnaires and from interim reports received through mail, email, or telephone conversations.  Participants 
will be asked to provide the name(s) and contact information for treating physicians and written consent to 
obtain medical records.  Treating physicians will be asked to complete a questionnaire related to the diagnoses 
or to provide relevant medical records.  Participants with medical record confirmed diagnoses of AMD will be 
sent follow-up questionnaires to assess progression of AMD. 
COSMOS Falls and Physical Performance 
Falls and decreased physical performance are major public health problems among older adults. Each year in 
the U.S., 30% of adults aged ≥65 years fall, resulting in increased risk of injury, hospitalization and death. 
Several lines of evidence suggest that flavanols, commonly found in cocoa, confer beneficial effects on muscle 
function and physical performance. The effects of supplemental cocoa flavanols on recurrent falls, injurious 
falls resulting in healthcare utilization, and musculoskeletal health, will be examined in a cost-efficient ancillary 
study. The benefits and/or risks of multivitamins on musculoskeletal health among the study population will 
also be assessed.   
Throughout the COSMOS intervention phase testing cocoa flavanols and a multivitamin, information on falls, 
fractures, and the use of medications for bone health was collected at baseline and on the periodic follow-up 
health questionnaires.  Information from the main trial questionnaires will be used to determine whether cocoa 
extract reduces risk of recurrent falls (defined as 2 or more falls per year), injurious falls resulting in healthcare 
utilization, and fractures.  A follow-up Fall Questionnaire will be sent to assess circumstances surrounding 
injurious fall(s) with healthcare utilization (e.g., reason for fall, location of fall) and medical records will be 
obtained for adjudication of the fall and fall-related injuries. 
Information obtained from the clinic sub-cohort (n = 603) at baseline and 2-years post randomization will be 
used to test whether cocoa flavanols improve physical performance as assessed by grip strength (by 
dynamometer), walking speed (6 meters), and the Short Physical Performance Battery (SPPB) that includes 
tests of walking speed, standing balance, and chair stands.  The effects of the study agents on changes in 
bone density will also be explored. 
Results from analyses of the biospecimens will be used to examine effect modification by changes in 
flavanol concentrations on the fall(s) and fractures outcomes. Parallel analyses of the multivitamin 
supplement also will be performed.  COSMOS provides a unique opportunity to maximally leverage 
existing resources to test, at minimal cost, efficacy of cocoa flavanols and/or a multivitamin on improving 
clinically meaningful musculoskeletal outcomes among older women and men in the U.S. 

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Dr. Carolyn Crandall, Professor of Medicine at the David Geffen School of Medicine, UCLA, is an investigator 
on the COSMOS Falls and Physical Performance ancillary study to COSMOS.  She will assist with design and 
conduct of the sub-study, adjudication of outcomes, interpretation of data, and presentation of the results.  
Mass General Brigham (MGB) staff will communicate with study participants to collect the sub-study 
questionnaires, signed authorization forms, and copies of medical records from healthcare providers.  Once 
received, the records will be scanned onto a secure MGB network server managed by the Brigham and 
Women’s Hospital Division of Preventive Medicine (DPM).  Using an encrypted laptop, Dr. Crandall will have 
access to identifiable data on the secure, web-based online medical record review/outcome adjudication 
system through the MGB Virtual Private Network (VPN).  No data will be transferred to Dr. Crandall or to the 
David Geffen School of Medicine at UCLA.  A Research Data Sharing Plan will be put into place. 
COSMOS Inflammaging and Epigenetic Aging 
The effects of cocoa extract and multivitamins on longitudinal change in biological aging will be examined in an 
ancillary study conducted in collaboration with investigators from Augusta University.  Accelerated epigenetic 
aging that comprises DNA methylation changes has recently emerged as a powerful, novel predictor for 
lifespan and health span, disease susceptibility, morbidity, and mortality risk.  DNA methylation is a major 
epigenetic process that regulates gene expression and can be modified by different bioactive compounds in 
foods.  In addition, human aging is characterized by chronic, low-grade inflammation, which has recently been 
termed inflammaging.  Inflammaging is exemplified by mild chronic elevation in blood levels of C-reactive 
protein (CRP) and several cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which 
increase with aging.  Inflammaging is a highly significant risk for both morbidity and mortality in the elderly, 
including cardiovascular disease.  
Biospecimens collected from 600 COSMOS participants at baseline and after 1- and 2-years of follow-up will 
be analyzed for changes in markers of DNA methylation (including AgeAccelHorvath, AgeAccelHannum, 
LAgeAccelGrim, AgeAcfcelPhono, and DNAm TLadjAge) and inflammation.  The relationship between cocoa 
extract and changes in epigenetic aging and inflammaging in relation to CVD will be evaluated.  Parallel 
assessments of multivitamins on these markers of biological aging and CVD outcomes will also be performed.  
This ancillary study will provide valuable insights into the underlying molecular mechanisms for two popular 
supplements (cocoa and multivitamins) and holds great promise for targeting by nutritional interventions. 
COSMOS Phase 1 Biomarker Assessments 
BWH will send approximately 1,100 blood samples from 400 COSMOS participants to the University of 
California at Davis (UCD) for the measurement of key biomarkers linked with both the cocoa extract and 
multivitamin interventions. The assay results will be integrated into the analyses for the COSMOS Mind, Web, 
and coronavirus disease 2019 (COVID-19) projects. No additional samples will be collected from participants. 
No protected health information (PHI) will be sent to UCD. 
COSMOS Phase 2 Biomarker Assessments 
BWH will send approximately 11,600 spot urine samples from 6,795 COSMOS participants to the University of 
Reading (UR) for the measurement of key biomarkers linked with both the cocoa extract and multivitamin 
interventions. The assay results will be integrated into the analyses for the COSMOS interventions. No 
additional samples will be collected from participants. No protected health information (PHI) will be sent to UR. 

COSMOS Protocol 
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Page 25 
9.2. COSMOS Cancer Tissue Study 
We plan to establish a biobank of tumor tissue and slides for the future examination of the mechanistic effect, if 
any, of multivitamin and cocoa flavanol use on risk and survival from common cancers, such as breast, 
bladder, prostate, and lung, among the COSMOS population.  The COSMOS trial provides a unique and cost-
efficient resource to elucidate the molecular mechanisms by which the study supplements exert their benefit(s).  
We plan to examine the biologic effect of multivitamins and cocoa flavanols by leveraging cutting-edge 
molecular and genomic technologies (including but not limited to immunohistochemistry, RNA-sequencing, 
whole genome sequencing, epigenomic assays) to better understand cancer etiology.   
To determine the feasibility of establishing a biobank of cancer tissue, we plan to conduct a pilot study to 
assess willingness of COSMOS participants to provide consent for their tissue samples to be collected and the 
success of obtaining tissue blocks and/or slides from hospitals and providers’ offices.  We will request samples 
only from those participants who have confirmed diagnoses of incident cancers.  As per study protocol, we will 
first request consent to review medical records from participants who self-report a new or recurrent cancer 
diagnosis on the periodic COSMOS health questionnaires.  For those who provide consent, we will obtain the 
relevant medical records from treating physicians or healthcare facilities.  Once the records are received, 
reviewed by COSMOS investigators, and the diagnoses are confirmed, we will send participants a letter to 
request their tissue samples.  Our goal is to conduct the pilot study in a sample of up to 80 participants with 
confirmed cases of incident cancers. 
9.3  Coronavirus disease 2019 (COVID-19) 
In response to the coronavirus disease 2019 (COVID-19) pandemic, we will send COSMOS participants email 
invitations for online REDCap surveys that have been prepared to collect critically needed, time-sensitive data 
on the epidemiology of COVID-19 in older adults, who have been disproportionately affected by the ongoing 
pandemic. 
COSMOS participants will be combined with participants in two other active, large-scale, long-term prospective 
studies conducted at our Division of Preventive Medicine, the VITamin D and Omega-3 TriaL (VITAL) (protocol 
#2009P-001217), and the Women’s Health Study (WHS) (protocol #2004P-001661), for a total of 52,000 
participants who will be sent the email invitation with the secure link to the COVID-19 survey.  Participants in 
these three studies have demonstrated interest, dedication, and continued participation in medical research 
and disease prevention through the completion of questionnaires and other study activities. 
Participants who provided email addresses and have indicated willingness to be contacted by email to 
complete surveys online will be sent the invitation with the secure link to the COVID-19 survey.  We will send 
reminder emails to non-respondents. The survey is consistent with our REDCap surveys sent and completed in 
the past and will collect critically important and time-sensitive information about symptoms, testing, diagnoses, 
treatments, severity of illness, and risk factors for the coronavirus.  If willing, anyone who reports having the 
coronavirus infection and/or COVID-19 hospitalization will be contacted to provide consent to review their 
medical records following standard procedures already in place for the study.   
COVID-19 surveys will be sent at three different time points spaced approximately one month apart to update 
participant status with regard to coronavirus testing, symptoms, diagnoses, and other relevant risk factors 
during this evolving pandemic. The data from these COVID-19 surveys will make seminal contributions to our 
understanding of the causes and consequences of coronavirus infection and COVID-19 during this pandemic.   

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COVID-19 is an ongoing global pandemic currently affecting the US, yet little is known about risk factors for 
illness, including more severe illness and indicators of recovery. COSMOS will collaborate with the 
Researching COVID to Enhance Recovery (RECOVER) study, a National Institutes of Health (NIH) COVID-19 
Initiative Project to address this issue. COSMOS will send an initial email to inform participants about this new 
research opportunity. Participants that are interested to learn more about the RECOVER study have the option 
to click on a secure REDCap link to view the invitation letter and brief screening survey. The COSMOS group 
will identify eligible and willing participants, and their screening information will be sent to the RECOVER group 
through a secure MGB server.   
10.0. Statistical Analysis  
In this 2x2 factorial trial, the primary aim is to compare the main effects of intention-to-treat with cocoa extract 
on incident CVD events, and multivitamins on rates of diagnoses of new cancers.   The primary analysis be 
based on the intention-to-treat principle and use the Cox proportional hazards model for time-to event data41 
and estimate the HR for each intervention using indicators for the specific treatment, controlling for the second 
intervention, and stratifying the baseline hazard by (at minimum) sex, age group, and recruitment center (WHI 
or BWH). P-values will be based on a score tests for each intervention hazard ratio.  Because the cohort 
consists of older women and men, competing risks due to deaths from other causes will be also be 
incorporated. Specifically, the primary analyses will estimate the cause-specific hazard and HR comparing 
intervention groups for each outcome by censoring individuals with deaths due to competing causes. We will 
estimate the cumulative incidence function for each comparison (multivitamin versus placebo, cocoa flavanols 
versus placebo) and plot the subdistribution of each endpoint over time.42,43  
The alternative Fine and Gray approach44 models the effect of treatment on the subdistribution hazard or 
directly on the cumulative incidence function. Although we will consider this model, Cox proportional hazards 
will be our primary analysis.  Additional analyses of composite endpoints that include total mortality will provide 
a practical approach to the evaluation of the impact of competing risks. 
In secondary analyses, we will examine effect modification by the other randomized intervention, gender, age, 
other key risk factors, time, and concomitant medications such as statins and aspirin. Interactions will be 
interpreted cautiously as hypothesis generating. We will also stratify by past randomization status in WHI trials. 
We will also consider baseline dietary intake and a subcohort of women and men with biomarker data analyzed 
as a case-cohort study using methods for proportional hazards regression.45 Because of frequency matching 
by age, we will use appropriate stratum-specific weighting of observations.46  
11.0. Data Management 
The COSMOS data repository will be a single centralized database maintained by BWH 
All pre-randomization participant data collected from all BWH participants and WHI participants who signed a 
COSMOS consent form are stored on the BWH data systems. Prior to the 12-month post-randomization 
phase, follow-up for missing and incomplete information is done by each institution separately but the data are 
stored centrally at BWH. Secure file transfer protocols are used to share data between the two institutions. 
Eligibility assignment during pre-randomization is performed by the WHI CCC for each participant and the data 
is transferred back to BWH securely. 
Separate web applications at each institution allow their respective staff to perform the necessary tasks. The 
CCC will implement systems to support recruitment and screening mailings, data entry, and scanning of forms 
for WHI participants who enroll into COSMOS; modify the outcomes processing system to accommodate 

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changes in outcomes collection required for WHI participants; and create datasets and reports to support study 
monitoring and analyses. BWH will be responsible for recruitment and screening of BWH participants; 
scanning of BWH forms; ancillary study and biospecimen project mailings; post-randomization form mailings 
beginning with the 12-month follow-up phase; and study pill dispensing. The CCC will support BWH’s 
participant unblinding efforts and create final datasets for analyses and data sharing purposes.  
Starting in September 2016, some study data will be collected electronically using REDCap (Research 
Electronic Data Capture), a free, secure, HIPAA-compliant web-based application hosted by the Partners 
HealthCare Research Computing, Enterprise Research Infrastructure & Services (ERIS) group. Vanderbilt 
University, with collaboration from a consortium of academic and non-profit institutional partners, has 
developed this software and workflow methodology for electronic collection and management of research data. 
Our research team will develop REDCap surveys that mirror the standard paper-based questionnaires used 
throughout the trial. REDCap provides features that can be used for a variety of research projects and provides 
an intuitive interface to enter data with real-time validation (automated data type and range checks). The 
system offers easy data manipulation with audit trails, reports for monitoring and querying participant records, 
and an automated export mechanism to common statistical packages (e.g., SAS). 
Participants’ names and contact information will be accessible only to staff members who need the information 
for their jobs. Endpoint and health-related questionnaire data will be stored in separate files from the 
processing data and will be accessible only to approved investigators and programmers. In these files, 
participants are identified only by study ID. 
11.1     Sending Data/Materials to Research Collaborators outside Mass General Brigham 
A deidentified data set will be sent to Dr. Linda Neal, a retired professional data analyst, for dementia research. 
The data sent will contain deidentified variables from the COSMOS Mind ancillary study tests outlined in 
Section 9.1. The data will be securely transferred using the Partners Secure File Transfer system. 
Limited data sets will be sent to Dr. Yu-Han Chiu at Penn State College of Medicine in Hershey, Pennsylvania 
and Dr. Soshiro Ogata at the National Cerebral and Cardiovascular Center in Suita, Japan for data analysis 
purposes. The data sets will contain descriptive, adherence, and outcome variables. The data will be securely 
transferred using the Partners Secure File Transfer system. 
12.0. Study Monitoring 
An independent Data and Safety Monitoring Board (DSMB) for COSMOS will be convened with appropriate 
expertise in clinical trials, epidemiology, biostatistics, and relevant clinical areas such as CVD and cancer. 
Representatives from the VITAL DSMB and the parallel WHI oversight committee (currently the DSMB) will be 
invited to participate. 
The role of the COSMOS DSMB will be to examine the unblinded data on adherence, endpoints and adverse 
effects and recommend continuation, alteration in study design, or early termination as appropriate to assure 
the ethical conduct of the study. 
Interim trial results will be assessed with the Haybittle-Peto rule,47,48 adjusting for multiple looks. In this method, 
interim results are compared to a z-score of 3 standard deviations (p=0.0027) throughout the trial. The final 
results may then be interpreted as having close to nominal significance levels. This rule appropriately requires 
very strong evidence for early stopping, is more conservative than the Pocock49 and O’Brien-Fleming50 rules 

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Page 28 
and the alpha-spending function,51 and can be conducted at convenient times without inducing statistical 
complexity.52 
While these rules are intended for the primary endpoints, the goal is to assess the overall balance of benefits 
and risks of the two agents. Thus, consideration will also be given to the secondary endpoints that are needed 
in the interpretation of overall results. The monitoring rules will serve as guidelines in evaluating the strength of 
the existing data regarding benefits and harms.  All decisions for continuation or stopping of treatment arms 
must be made after examining the totality of evidence, including other trial data, on these agents. Each 
treatment arm comparison will be considered independently of the other, i.e., one intervention may be stopped 
while the other may continue without any disruption in the planned follow-up.   
13.0. Quality Assurance 
Redundancies will be built into the data processing systems to ensure accurate recording of data and proper 
follow-up. All research forms will be scanned in and the data read by a character-recognition software program 
(Cardiff TeleForm). Inconsistent, and unclear data will be reviewed by a verifier who will edit misread variables. 
Information from forms that cannot be scanned will be copied onto new forms.  The new data forms will be 
scanned and the original, damaged forms will be filed for future reference, if necessary.  All data will undergo 
additional within-form and across-time checks to verify accuracy. Following data entry, all questionnaire 
responses that require additional follow-up for missing data, participant comments on the form or for endpoint 
validation will be manually reviewed to ensure correct processing and accurate follow-up.  
Great care will be taken to ensure that participants receive their randomly assigned drugs. Upon receipt of drug 
shipments from the manufacturer, each of the four drug groups will be stored in segregated areas. A random 
sample of drugs bottles or calendar packs will be pulled from each drug group and blindly tested to insure that 
the packaged contents match the study label. At the time of packaging for shipment to individual participants, 
listings will be divided according to drug group assignment and only one group will be packaged at a time. The 
packaging area will be cleaned and cleared prior to packaging and shipment of the next drug group. If drug 
packages are returned by the postal service as undeliverable or declined by a participant, the contents of the 
package will be blindly tested as an additional level of quality control. 
14.0. Study Administration and Organization  
The BWH, WHI CCC, WHI Regional Centers, and WHI and VITAL investigators have worked closely to 
develop leadership and collaborative infrastructure. The Steering Committee, Ancillary Studies Committee, 
Publications and Presentations Committees, and other committees will include both WHI and BWH 
representatives. We expect to include all interested investigators in future projects involving the trial, and in the 
leadership and conduct of ancillary studies.    
15.0. Study Timeline  
The study plan assumes that recruitment, placebo run-in and randomization procedures will be completed for 
all 22,000 participants within 1-3 year of study initiation.  This will allow an average of 4 years of intervention 
and follow-up; and 6 months for trial close-out and analyses (Table 2):  
Table 2.  Anticipated timeline for completion of the COSMOS trial  
 
 
 
 
Activity 
Y1 Y2 Y3 Y4 Y5 

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16.0.  Ancillary Studies 
Ancillary studies to the COSMOS will proceed through the WHI Ancillary Studies Committee approval process.  
The WHI DCC (Project Coordinator) will provide administrative support as needed for ancillary study 
committee activities related to this trial. 
17.0. Appendix 
• 
COSMOS Consent 
• 
Cover Letter for WHI participants for COSMOS 1 
• 
Cover Letter for non-WHI participants for COSMOS 1 
• 
COSMOS 1 (Screening form) 
• 
COSMOS 2 (Baseline form) 
• 
COSMOS 3 (Post run-in Adherence form) 
• 
COSMOS Food Frequency Questionnaire 
• 
COSMOS 6-Month Questionnaire 
• 
COSMOS 12-Month Questionnaire 
• 
COSMOS 18-Month Questionnaire 
• 
COSMOS 2-Year Questionnaire 
• 
COSMOS Food Frequency Questionnaire 2 
• 
COSMOS 30-Month Questionnaire 
• 
COSMOS 3-Year Questionnaire 
• 
COSMOS 42-Month Questionnaire 
• 
COSMOS 4-Year Questionnaire 
• 
COVID-19 Survey 
• 
June COVID-19 Survey 
• 
August COVID-19 Survey 
• 
COSMOS January 2021 Questionnaire 
• 
COSMOS Obs 1 Questionnaire 
• 
COSMOS Obs 2 Questionnaire 
• 
COSMOS Obs 3 Questionnaire 
Finalize protocol and arrangements for study pills 
X 
 
 
 
 
IRB approvals  
X 
 
 
 
 
Subject recruitment 
X 
X 
X 
 
 
Placebo run-in 
X 
X 
X 
 
 
Treatment and follow-up 
X 
X 
X 
X 
X 
Biomarker and blood pressure collection 
X 
X 
X 
X 
X 
Clinic-based assessments 
X 
X 
X 
X 
X 
Study closeout 
 
 
 
 
X 
Analyses and publication of final manuscripts 
 
 
 
X 
X 

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2. 
Aron PM, Kennedy JA. Flavan-3-ols: nature, occurrence and biological activity. Mol Nutr Food Res 
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3. 
Waterhouse AL, Shirley JR, Donovan JL. Antioxidants in chocolate. Lancet 1996;348:834. 
4. 
Baba S, Osakabe N, Natsume M, Yasuda A, Takizawa T, Nakamura T, Terao J. Cocoa powder 
enhances the level of antioxidative activity in rat plasma. Br J Nutr 2000;84:673-680. 
5. 
Kondo K, Hirano R, Matsumoto A, Igarashi O, Itakura H. Inhibition of LDL oxidation by cocoa. Lancet 
1996;348:1514. 
6. 
Rein D, Paglieroni TG, Pearson DA, Wun T, Schmitz HH, Gosselin R, Keen CL. Cocoa and wine 
polyphenols modulate platelet activation and function. J Nutr 2000;130:2120S-2126S. 
7. 
Rein D, Paglieroni TG, Wun T, Pearson DA, Schmitz HH, Gosselin R, Keen CL. Cocoa inhibits platelet 
activation and function. Am J Clin Nutr 2000;72:30-35. 
8. 
Kurosawa T, Itoh F, Nozaki A, Nakano Y, Katsuda S, Osakabe N, Tsubone H, Kondo K, Itakura H. 
Suppressive effect of cocoa powder on atherosclerosis in Kurosawa and Kusanagi-
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Grassi D, Necozione S, Lippi C, Croce G, Valeri L, Pasqualetti P, Desideri G, Blumberg JB, Ferri C. 
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Heiss C, Dejam A, Kleinbongard P, Schewe T, Sies H, Kelm M. Vascular effects of cocoa rich in flavan-
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Karim M, McCormick K, Kappagoda CT. Effects of cocoa extracts on endothelium-dependent 
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Ramiro E, Franch A, Castellote C, Andres-Lacueva C, Izquierdo-Pulido M, Castell M. Effect of 
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Ried K, Sullivan TR, Fakler P, Frank OR, Stocks NP. Effect of cocoa on blood pressure. Cochrane 
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15. 
Jalil AM, Ismail A, Pei CP, Hamid M, Kamaruddin SH. Effects of cocoa extract on glucometabolism, 
oxidative stress, and antioxidant enzymes in obese-diabetic (Ob-db) rats. J Agric Food Chem 
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16. 
Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, Thomas PR, Betz JM, Sempos CT, Picciano 
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17. 
Gahche J, Bailey R, Burt V, Hughes J, Yetley E, Dwyer J, Picciano MF, McDowell M, Sempos C. 
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Brief 2011:1-8. 
18. 
Li K, Kaaks R, Linseisen J, Rohrmann S. Vitamin/mineral supplementation and cancer, cardiovascular, 
and all-cause mortality in a German prospective cohort (EPIC-Heidelberg). Eur J Nutr 2012;51:407-
413. 
19. 
Park SY, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Multivitamin use and the risk of mortality 
and cancer incidence: the multiethnic cohort study. Am J Epidemiol 2011;173:906-914. 
20. 
Larsson SC, Akesson A, Bergkvist L, Wolk A. Multivitamin use and breast cancer incidence in a 
prospective cohort of Swedish women. Am J Clin Nutr 2011;91:1268-1272. 
21. 
Neuhouser ML, Wassertheil-Smoller S, Thomson C, Aragaki A, Anderson GL, Manson JE, Patterson 
RE, Rohan TE, van Horn L, Shikany JM, Thomas A, LaCroix A, Prentice RL. Multivitamin use and risk 
of cancer and cardiovascular disease in the Women's Health Initiative cohorts. Arch Intern Med 
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22. 
Stevens VL, McCullough ML, Diver WR, Rodriguez C, Jacobs EJ, Thun MJ, Calle EE. Use of 
multivitamins and prostate cancer mortality in a large cohort of US men. Cancer Causes Control 
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23. 
Jacobs EJ, Connell CJ, Patel AV, Chao A, Rodriguez C, Seymour J, McCullough ML, Calle EE, Thun 
MJ. Multivitamin use and colon cancer mortality in the Cancer Prevention Study II cohort (United 
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