COcoa Supplement and Multivitamin Outcomes Study-Mind
Conditions: Cognitive Impairment, Dementia, Aging
Sponsor: Wake Forest University Health Sciences

COSMOS-Mind Protocol, v05: 14Jun2017 
 
 
 
 
 
Official Title:  COcoa Supplement and Multivitamin Outcomes Study-Mind 
NCT:  NCT03035201 
Related NCT:  NCT102422745 
IRB-Approved Date:   6/15/2017 
 

COSMOS-Mind Protocol, v05: 14Jun2017 
 
 
COSMOS-Mind PROTOCOL 
 
1. BACKGROUND  
 
 
This study will be conducted in partnership with a large funded randomized controlled trial, the COcoa 
Supplement and Multivitamin Outcomes Study (COSMOS),1,2 and will examine the potential cognition-
protecting effects of high-potency cocoa flavanol extract, with and without co-administration of a standard 
multivitamin (MTV) in adults 65 years and older, concurrently with their evaluation of cardiovascular disease 
(CVD) and cancer endpoints.  
 
Cocoa Flavanol Effects on Cardiovascular Health 
 
 
Cocoa, in its unprocessed form, contains high quantities of catechins and epicatechins, a subclass of 
flavonoids known as flavanols,3,4 and theobromine, an alkaloid of the cacao bean with vasodilation properties.5 
Although the benefits of flavonoids have been studied for years, the health-promoting effects of cocoa 
flavanols caught the attention of the scientific community and public when low rates of hypertension and 
mortality due to CVD were reported in Kuna Indians living in the remote San Blas islands off the coast of 
Panama – protections that were lost with migration to urban areas. Extensive studies of the Kunas’ lifestyle 
identified their dietary exposure to large amounts of cocoa flavanols as the primary contributing factor.6 
Observational studies consistently demonstrate an inverse association between cocoa flavanol consumption 
and risk of CVD,7-10 and in clinical trials cocoa flavanols have robust favorable effects on cardiovascular 
health,11-15 influencing endothelial function and flow-mediated dilation,16,17 blood pressure,18-20 platelet adhesion 
and aggregation,21,22 lipid profiles,20,23,24 antioxidant capacity,20,25,26 systemic inflammation,27 and insulin 
sensitivity and β-cell function.20,28,29 Pilot trials of up to 100 participants with 4-12 weeks of varying doses of 
cocoa flavanols in different patient groups provide consistent evidence for cardiovascular benefits at doses 
>700 mg/day and without adverse events.20,29-33 However, the benefits of cocoa flavanols on clinical CVD 
events in older adults have yet to be examined in a definitive trial.  
 
Cocoa Flavanol Effects on Cognition and Brain Function 
 
 
COSMOS-Mind will examine whether cocoa flavanols protect and even enhance cognitive function in older 
adults, an appropriate extension of the parent trial given the robust association between vascular and cognitive 
health.34-36 This association was the focus of a recent study of over 9,000 older adults drawn from the National 
Alzheimer’s Coordinating Center: increased vascular risk, which included history of CVD and atrial fibrillation, 
predicted faster rates of cognitive decline in cognitively normal adults and in individuals with mild cognitive 
impairment (MCI).36 Dietary consumption of cocoa flavanols may slow this decline through its beneficial effects 
on cerebral vasodilation, and thus on brain blood flow and perfusion, and angiogenesis.37,38 Epicatechin, the 
most common flavanol in cocoa, is rapidly absorbed, readily crosses the blood-brain barrier, can be detected in 
the brain,39-41 and likely has accumulating physiological effects at high doses.40,42 This evidence for brain 
penetrance provides an important foundation for other cognition-enhancing mechanisms of flavanols at the 
neuronal level.43,44  
 
The effects of cocoa flavanols on cognition have been examined in animal studies for years, and 
consequently, putative underlying mechanisms related to endothelial function and pivotal signaling cascades 
for neuronal activity and viability are well described.38 However, these mechanisms have not been fully 
explored in controlled clinical studies. Much of the support for a cognition-enhancing effect of flavanols in 
healthy older adults comes from observational studies, and a few small but promising controlled trials.45,46 In 
one large prospective study of 1640 older adults (≥65 yrs) followed for 10 years,47 dietary intake of flavonoid-
rich food (dark chocolate, wine, tea) was positively correlated with cognitive performance at baseline and over 
time in a dose-dependent manner. At the end of follow-up, participants in the lowest quartile for flavonoid 

COSMOS-Mind Protocol, v05: 14Jun2017 
 
 
intake had lower Mini-Mental State Examination (MMSE) scores vs. those in the highest quartile. A favorable 
dose response of flavonoid intake on cognition was also reported in a large cross-sectional Norwegian study 
for a more extensive set of outcomes measuring attention and task-switching, verbal fluency, and spatial 
perception.45 Regular flavonoid intake has also been linked to lower rates of prevalent cognitive impairment48 
and incident dementia.49,50  
 
Only a handful of controlled trials have examined the potential benefits of regular cocoa flavanol intake on 
cognitive function in older adults. While a few studies have failed to show cognitive benefits of cocoa 
flavanols,37,51-53 others provide compelling support to suggest that regular use of the high potency form of the 
extract may protect and possibly enhance cognitive function,20,54,55 a variability that likely reflects differences in 
methodology and/or extract formulation. In a small randomized, double-blind, 3-month trial of a high potency 
cocoa flavanol extract that is very similar to that administered in COSMOS, Brickman, et al. reported increased 
blood flow in the dentate gyrus and an associated improvement on a validated dentate gyrus-dependent 
memory task in older adults (50-69 years).54 The strongest support for the proposed study is provided by the 
results of the Cocoa, Cognition, and Aging Study, a double-blind, 8-week randomized controlled trial of cocoa 
flavanols in 90 cognitively healthy older adults20 and in 90 individuals with amnestic mild cognitive impairment 
(MCI)55 at high risk for AD dementia. Participants consumed a daily drink with a high (993 mg) or medium (520 
mg) dose, versus a low (45 mg) dose, of cocoa flavanols. Compliance exceeded 97% without adverse events. 
In both the healthy and MCI cohorts, performance on tests of attention and processing speed, task-switching 
and working memory, verbal fluency, and the global cognitive composite outcome improved for those in the 
high- and medium-dose groups relative to the low-dose group. In these participants, cocoa flavanols also 
lowered systolic and diastolic blood pressures, increased insulin sensitivity, and reduced a potent marker of 
oxidative stress. In both groups, a favorable treatment effect on insulin sensitivity was the primary determinant 
of cognitive response, consistent with a substantial body of work linking glucose regulation and cognitive 
function in older adults.56-59 This insulin sensitizing effect of cocoa flavanols, also reported by others,13 has 
important implications for older adults for whom the combined prevalence rate of type 2 diabetes and 
prediabetes exceeds 75% nationwide.60 These findings demonstrate the potential efficacy of cocoa flavanol 
supplementation in the dose range proposed, and set the stage for this trial in cognitively healthy and mildly 
impaired older adults that will test whether regular intake of high dose cocoa flavanols can protect cognitive 
function and thus slow cognitive decline associated with normal and pathological aging, including AD. The 
extract’s excellent tolerability profile provides added translational value. 
 
Micronutrient Supplementation (Multivitamin) Effects on Cognition 
 
 
COSMOS-Mind will also test whether daily use of a standard multivitamin benefits cognition in older adults. 
Although essential nutrient deficiencies in older adults have been associated with a higher risk of cognitive 
decline and dementia,61 the results of other studies examining MTV use for cognitive benefit remain 
controversial.62 Multivitamin use alone or with other therapies to enhance cognitive function in older adults has 
not been adequately examined in large randomized controlled trials (RCTs).63 Controlled trials of a single 
nutrient focused on folic acid with or without other B vitamins,64,65 omega-3 fatty acids,66,67 and vitamin D61,68,69 
have yielded mixed results, which could reflect the absence of a cognitive benefit or limitations in study design. 
Some of the design issues that contribute to this variability relate to the specific micronutrients administered 
and their interactions with one another, the cognitive tests selected, and variability in participant demographics 
and nutritional status.63,70 In the population-based Canadian Study of Health and Aging examining dementia 
onset in adults aged 65 years and older, participants reporting regular use of MTVs at baseline were less likely 
to experience significant cognitive decline during the 5-year follow-up.71 In a large RCT recruiting from multiple 
health care facilities in Scotland, daily use of a balanced multivitamin for 1 year improved verbal fluency, but 
only for those at least 75 years old or with a possible micronutrient deficiency at baseline (as per a risk 
questionnaire).72 The Physician’s Health Study (N=5947, ≥65 years old) reported no effect of multivitamin use 
on cognition in older men.73 These studies raise the possibility that micronutrient supplementation may only 
benefit cognitive function in adults who are vulnerable due to advanced age or poor nutrition. However, the 
effects of MTVs on cognition in older women have not been adequately examined in a large RCT.   

COSMOS-Mind Protocol, v05: 14Jun2017 
 
 
 
2. OBJECTIVES 
 
     COSMOS-Mind is an ancillary cognitive study to the large randomized double-blind, placebo-controlled 
COSMOS trial, coordinated through Brigham and Women’s Hospital (BWH). The parent trial will test whether 
high-potency cocoa extract supplement administered alone or in combination with a standard multivitamin 
reduce risks of CVD and cancer in older adults.  COSMOS-Mind will test whether 3 years of treatment with 
these supplements improves cognitive function and reduces risk of cognitive impairment, including AD and 
other forms of dementia.   
 
Primary Aim 
 
• 
Test whether random assignment to daily cocoa extract (capsule containing 750 mg/d flavanols, including 
75 mg (-)-epicatechin, and 90 mg theobromine), compared to placebo, has favorable effects on a 
composite measure of cognitive function, over 3 years of follow-up in men and women who are 65 years 
and older 
 
Secondary Aims 
 
• 
Examine the effects of MTV use over 3 years of follow-up, relative to placebo, on a composite measure of 
cognitive function 
• 
Assess treatment effects on incident MCI, and AD and other related dementias 
• 
Compare intervention effects on cognitive domains of executive function and episodic memory 
 
Tertiary Aims 
 
• 
Examine consistency of treatment response for subgroups defined by age, sex, body mass index, baseline 
cognitive status, CVD, and type 2 diabetes 
• 
Examine treatment effects on measures of sleep quality, depressive symptoms, and subjective memory 
concerns  
• 
Share COSMOS-Mind data with the parent trial and its ancillary studies to expand its scientific impact  
 
3. DESCRIPTION OF PARENT TRIAL (COSMOS) 
 
 
COSMOS is supported through an investigator-initiated award from Mars SymbioScience (PIs: Drs. 
Manson and Sesso of BWH), and is a randomized, double-blind, placebo-controlled, 2x2 factorial clinical trial in 
18,000 older women and men. The trial is testing a patented, well-studied cocoa extract supplement (capsules 
containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) and a daily MTV 
(Centrum Silver®, provided by Pfizer) in the prevention of CVD and cancer. COSMOS participants will be 
recruited from 2 large national cohorts of older adults (Women’s Health Initiative Extension Study 
[observational; N=73,991]; VITamin D and OmegA-3 TriaL [eligible but unenrolled candidates; N=89,373]). The 
mean treatment and follow-up period in COSMOS will be 4 years. Participants will be asked to forego personal 
use of MTV and cocoa extract supplements while in the trial. Adherence and dietary intake of non-study 
supplements will be assessed via self-report using semi-annual questionnaires and pill count with nutrient 
biomarker measurements in a subset. A 3-month placebo run-in will eliminate those with poor compliance 
before randomization.  
 
4. STUDY POPULATION 
 
Inclusion and Exclusion Criteria 
 

COSMOS-Mind Protocol, v05: 14Jun2017 
 
 
 
COSMOS-Mind will include 2500 participants from the parent trial who are at least 65 years of age, with 
approximately equal distribution of women and men.  
 
The study will exclude participants with insulin-dependent diabetes. Insulin therapy, often associated with 
chronic hyperinsulinemia, can worsen cognition74 and therefore potentially mask beneficial effects of the cocoa 
flavanols. COSMOS participants co-enrolled in the WHI Memory Study (WHIMS) will be excluded given their 
prior exposure to COSMOS-Mind cognitive tests. Also, participants who are unable to complete the baseline 
cognitive assessment will not be permitted to continue in the study. Adults with dementia will likely self-select 
out of enrollment in COSMOS-Mind, or be excluded given the demands of the placebo run-in period required 
for COSMOS. For the few with mild dementia who may enroll in COSMOS-Mind, randomization will ensure 
equal distribution by treatment assignment. Pre-enrollment cognitive assessments to identify dementia are not 
feasible for this large simple trial.  
 
Recruitment and Consenting 
 
 
Eligible COSMOS participants will be approached for enrollment in COSMOS-Mind and a second cognitive 
ancillary study (“COSMOS-Web”: involves a brief online computer assessment) using a single approach letter 
and recruitment flyer during the placebo run-in phase of the COSMOS trial. These materials provide 
information about COSMOS-Mind, expectations of participants, what is provided to participants, and how to 
enroll in the sub-study. Participants can choose to participate in one, both, or neither sub-study and will let the 
BWH Coordinating Center know of their decision by completing and returning a provided form. Consent to 
participate will be implied when participants indicate their willingness to participate in COSMOS-Mind on this 
form or by informing the COSMOS team by telephone or email. Implied consent will be used given the low 
participant burden and low risk associated with study participation as per Wake Forest School of Medicine IRB 
accepted practices.  
 
Once enrolled, the COSMOS team at BWH will provide contact information and other parent trial outcomes 
for COSMOS-Mind participants to the Wake Forest COSMOS-Mind team using a secure web-based data 
transfer system. This seamless exchange of information between sites will permit timely accounting to ensure 
that the targeted demographics for enrollment are achieved (e.g. gender, age, race, ethnicity). 
  
5. OUTCOMES 
 
 
     Face-to-face assessments of cognitive functioning are expensive in large multi-site studies and thus 
telephone-based protocols have been developed and validated. Telephone-based assessments have been 
used successfully in other studies and provide a valid and cost-effective method for tracking changes in 
cognitive status, including the development of MCI and dementia.  
 
COSMOS-Mind will administer a telephone cognitive assessment to all participants annually by trained and 
certified staff of the Wake Forest COSMOS-Mind team. On the initial COSMOS-Mind call, consent to 
participate in the study will be confirmed and a brief hearing test will be administered to assess the participant’s 
ability to successfully complete the interview. The interview will be 45 to 60 minutes in duration, and will include 
social time to support the relationship, and time to complete the hearing screening, cognitive tests, and 
questionnaires. The assessment battery consists of 6 validated tests and 3 validated questionnaires. A fourth 
validated questionnaire may be administered to a knowledgeable friend or family member (informant) identified 
by the participant if cognitive scores fall below pre-specified thresholds on a test of global cognition (i.e., 
TICSm) at any assessment.  
 
A secure web-based call tracking system will be used to monitor participant contact, assessment dates, 
and attempts to complete interviews. Standard administration procedures of the telephone cognitive 
assessment will be for examiners to first record participants’ responses on paper versions of the tests and then 
at a later time, enter the data into a dedicated and secure web-based database management system. As a 
quality assurance measure, each administration of the cognitive battery will be electronically audio-recorded to 
assist the examiner in scoring and to allow data quality assurance checks. Examiners will be trained and 
certified before administering their first assessment to a participant. Annual re-certification will be required. 

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Hearing Assessment 
 
 
Before administration of the cognitive test battery, each participant will be asked a set of standardized 
questions: “Do you usually have trouble hearing when one person speaks to you?” “Do you usually have 
trouble hearing over the phone?” “Can you hear me well enough?” “Do you use a hearing device?” and “Is it in 
place?” and asked to repeat, “I have a cat so all I need is a dog.” Based on the participant’s responses, the 
examiner will adjust his/her test administration as needed. If hearing acuity is deemed significantly impaired, 
the examiner will terminate the assessment and the participant will not be permitted to continue in the study.  
 
Cognitive Assessment  
 
 
Telephone Interview for Cognitive Status-modified (TICSm) measures global cognitive function.75 Fourteen 
items assess orientation, attention, language, learning and memory, psychomotor skills and abstraction. A 
modification to the original TICS added a second free recall trial to assess delayed memory for the 10-item 
word list.76 In COSMOS-Mind, a third recall trial will be administered 15 minutes after this second recall trial, to 
quantify long delayed memory for the list. The TICSm has been previously validated for administration in older 
adults75-79 and used in large-scale epidemiological studies of cognitive impairment.80 The TICSm correlates 
highly with other measures of global cognitive function, including the Mini-Mental State Exam (r=0.86), the 
Clinical Dementia Rating scale (r=-0.75), and with comparable cognitive tests administered face-to-face.79,81-83 
The TICSm has excellent sensitivity (0.87) and specificity (0.89) to differentiate older persons with and without 
dementia84 and to identify amnestic MCI,85 and scores are normally distributed in population studies.86  
 
 
Immediate and Delayed Story Recall (SRI & II) measures verbal memory.87 Participants are read a short 
story of 25 distinct elements, and are asked to recall as many elements as possible immediately after hearing 
the story (SRI) and again 15-20 minutes later (SRII). Alternate parallel forms of Story Recall will be 
administered from one annual assessment to the next, in counterbalanced order across participants, to 
minimize practice effects.  
 
 
Oral Trail Making Test (OTMT)88,89 is a modified version of the original Trail-Making Test (TMT)90 that 
measures attention (Part A) and executive function (Part B). The OTMT is highly correlated with the original 
TMT.91 For Part A, participants are asked to count from 1 to 25 as quickly as possible. For Part B, participants 
recite numbers and letters in an alternating fashion (1-A-2-B-3-C…13) as quickly as possible. Time to complete 
each task (seconds) is recorded.  
 
 
Verbal Fluency is a measure of language accessibility and will be assessed using two tasks. Category 
Fluency requires participants to name as many exemplars of a semantic category as possible in 1 minute; two 
trials will be administered (categories = animals, vegetables). Letter Fluency requires participants to name as 
many words that begin with a specific letter of the alphabet in 1 minute; two trials will be administered (letters = 
F, L).92  
 
 
Number Span Test (NST)93 measures simple attention and working memory (i.e., ability to manipulate 
transitory information in short-term memory). This task requires the participant to repeat a series of single-digit 
numbers of increasing span length, first in the same order as presented by the examiner (Number Span 
Forward) and subsequently in the reverse order (Number Span Backward). Number of correct responses is 
recorded. 
 
 
Digit Ordering Test (DOT)93 is a task of working memory. Participants are read a series of single numerical 
digits and are asked to recite the numbers in order from lowest to highest (e.g., ‘2-7-1’ would be reordered as 
‘1-2-7’). For each span length, 2 trials are administered. Span is increased by 1 number until participants are 
unable to successfully complete both trials of a given span length. Number of correct responses is recorded. 

COSMOS-Mind Protocol, v05: 14Jun2017 
 
 
 
Additional Measures 
 
 
Cognitive Change Index (CCI)94 is a self-report questionnaire listing common experiences (e.g., “recalling 
conversations a few days later”, “remembering names and faces of new people”) and participants indicate 
amount of perceived change over a specified duration in the past (e.g., 5 years) using a Likert scale. To reduce 
participant burden, only the first 12 questions that address subjective memory concerns will be used to 
calculate the CCI score. The same 12-item subscale is used in the large multicenter Alzheimer’s Disease 
Neuroimaging Initiative-2 study.  
 
 
Geriatric Depression Scale-Short Form (GDS-SF) measures depressive symptom severity,95,96 which is 
known to affect cognitive function. This 15-item (Yes/No) questionnaire can be administered orally, and has 
excellent psychometric properties and normative data.97,98 Participants who score >8 on this scale or whose 
general responses to examiners’ questions suggest significant emotional distress will also receive the 
supplemental Emotional Distress Test, which includes standardized questions about depressive severity and 
suicidal ideation. If a participant indicates any suicidal inclination, a study clinician experienced in the 
assessment and treatment of geriatric psychiatric disorders (Dr. Rapp) will be informed, and will contact the 
participant to evaluate risk and make recommendations for follow-up. 
 
 
Women’s Health Initiative Insomnia Rating Scale measures sleep disturbance and insomnia, which are 
known to impact cognitive function. This 5-item self-report questionnaire has excellent reliability and construct 
validity, and is sensitive to change over time.99,100 
 
Adjudication of Cognitive Status to Identify MCI, AD and Other Dementias 
 
 
COSMOS-Mind will use the same procedures for ascertaining MCI and probable dementia (including AD) 
that were developed for WHIMS. All participants will be asked to identify a reliable informant at the time of the 
first telephone contact who could provide information about the participant’s cognitive and functional status. 
After each telephone cognitive assessment, suspected cases of cognitive impairment will be identified when 
TICSm<31, or, in follow-up Years 1-3 when the TICSm score drops by 0.5 of a standard deviation relative to 
age-appropriate normative data. For these participants, a trained interviewer will contact their informant to 
conduct a structured interview to complete the Dementia Questionnaire (DQ). This interview includes questions 
about current cognitive and behavioral functioning, and medical events and conditions that could impact 
cognition (e.g., stroke, psychiatric disorders).  
 
In Years 4 and 5, after the planned follow-up annual evaluations are completed, all available test results 
and medical information for participants who triggered a DQ at any time during the study will be provided to 2 
independent dementia experts. The information reviewed will include: cognitive data; self-report questionnaires 
about cognitive concerns, depression, sleep disturbances, and information on hospitalizations, medications 
and disabilities; informant responses on the DQ; and relevant health information available through the parent 
trial (including cardiovascular events and cancers). MCI classifications will include amnestic single domain, 
amnestic multi-domain, non-amnestic single domain, or non-amnestic multi-domain. If the adjudicator dyad 
agrees on the primary classification (MCI, probable dementia), no further discussion will occur; if the dyad 
disagrees, the case will be discussed by the entire adjudication panel until consensus is reached. 
Disagreements regarding MCI sub-classifications will be resolved within dyads and, if not possible, by the 
entire adjudication panel. For participants who receive a classification of ‘dementia,’ a letter will be sent to 
notify them that the test results indicated a possible cognitive impairment, and to encourage follow-up with a 
physician and further evaluation. 
 
 
6. STATISTICAL CONSIDERATIONS 
 

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The primary outcome for COSMOS-Mind is a composite measure of cognitive function that combines 
individual assessments of global cognitive function (TICSm), memory (SR), and executive function (OTMT, 
Verbal Fluency, NST, DOT). The composite provides a quantifiable measure of cognitive function across 
multiple domains and greater statistical power than individual measures even if the intervention effect varies 
moderately from one individual measure to another. It consolidates type 1 error into a single outcome. 
Secondary analyses, described below, will examine intervention effects on the constituent measures of the 
composite score. 
 
The primary hypothesis is that random assignment to high potency cocoa flavanol extract compared to 
placebo will result in a mean difference over time in the global cognitive composite score. This hypothesis will 
be tested using 2-tailed type 1 error of 0.05. Inference will be based on the marginal effect estimated from a 
factorial study design, and a generalized linear model101 with the dependent variable consisting of all measured 
annual changes from baseline across years of follow-up on every participant, regardless of adherence (i.e. 
intent-to-treat). Data from the individual tests will be combined using a multivariate analysis of covariance 
(MANOVA) model within this framework with adjustment for sex, education, and age. In this model, all 
observed data can be included without special procedures for missing data, provided they are missing at 
random. The estimated differences will be combined using the ordinary least squares global test statistic.102,103 
This statistic is the sum of the estimated differences of the individual tests divided by their standard errors, 
which produces a test statistic that is approximately normal with mean zero under the null hypothesis of no 
difference. Its standard error will be computed from the estimated correlation matrix of the treatment group 
differences. Cocoa flavanol effects will be examined by comparing cognitive response to active cocoa extract 
vs. its placebo, regardless of assignment to active MTV or its placebo.  
 
Secondary and tertiary aims. COSMOS-Mind will assess the relative effects of assignment to MTV using 
parallel analyses to those described above. The study will also assess whether effects of the two treatments 
interact on the primary outcome, adding a term to the model used in the primary hypothesis. If so, results from 
the primary marginal comparisons will be qualified. Individual cognitive test scores will be analyzed – 
paralleling the strategy used to test the primary hypothesis – in supporting analyses. The randomization effects 
on tertiary outcomes including cognitive complaints, sleep quality, and depressive symptoms will be assessed 
similarly to the intervention models used in the primary and secondary aims, and further tests will determine 
whether the treatments interact with respect to tertiary outcomes. Linear contrasts will be used to estimate 
treatment effects at 3 years. Tests of interactions will also assess the potential moderating effect of treatments 
among subgroups formed by age (<70 or >70 years old), sex, BMI (<25, 25-29, >30 kg/m2), baseline cognitive 
function (median split on TICSm), cognitive complaints (median split on CCI), depressive symptoms (median 
split on GDS-SF), hypertension, and diabetes; additionally, the preceding variables will also be assessed as 
continuous moderators of the intervention effects. The distribution of follow-up times to MCI and dementia will 
be assessed with proportional hazards regression. COSMOS-Mind will incorporate CVD and cancer events 
(from the parent trial) as change-points in the primary analyses to assess their impact on post-event cognitive 
trajectories. When needed, transformations (e.g. Box-Cox, rank, probit) will be used to improve the symmetry 
of residual distributions.  
 
Interim Testing 
 
     No interim monitoring of treatment effects on cognitive outcomes is planned. COSMOS-Mind investigators 
will remain masked to treatment assignment until the parent trial is completed.  Routine reports will assess 
retention, data completeness and quality, and cognitive trajectories over time. These reports will be sent to the 
COSMOS Coordinating Center for inclusion in DSMB reports. 
 
Statistical Power 
 
 
Longitudinal sequences of cognitive test scores from the WHIMS-ECHO study (N=2,878; 1-6 years of 
annual telephone assessments) were used to calculate the longitudinal covariance of measures in a simulation 
analysis. Loss-to-follow-up was set to accumulate at 5% per year, as per rates observed in WHIMS.104 Based 

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on previous studies,20,55 the intervention effect appears quickly and is sustained over time. Calculations are 
based on 2-sided tests with type 1 error set to 0.05 and 90% power for the primary outcome of a composite 
across all cognitive tests. Based on these and other projections, the 2500-person sample in COSMOS-Mind 
will provide >90% power to detect a sustained effect size of 0.10 SD and a waning effect size that initially is 
0.15 SD; it also provides some leeway should the assumptions made above be not fully realized. Limiting 
follow-up to 3 years allows a more extended enrollment and analysis period, and reduces the number of 
assessments.  
 
7. CONFIDENTIALITY 
 
 
Appropriate measures will be in place to protect against risk of disclosing confidential information. The data 
will be collected for research purposes only. All paper records of the telephone assessments will be stored in 
locked cabinets in locked rooms, accessible only to the COSMOS-Mind investigators and staff. Participants will 
be assigned a unique study identifier code on all study questionnaires and forms. All electronic data – including 
the master list pairing participants’ names and codes, recordings of telephone assessments, personal health 
information, and study outcomes – will be stored in password-protected files on a secure network in a secured 
area. This network is protected with frequently-updated anti-virus and anti-Trojan software, limited file sharing 
and file permissions to approved users only, and automated monitoring of access attempts; these procedures 
have successfully maintained security for many multicenter clinical trials coordinated by Wake Forest. 
COSMOS-Mind and COSMOS will develop data transfer procedures and protocols using password protection 
and encryption, to permit seamless and secure exchange of information. Safety monitoring will be provided by 
the DSMB of the parent trial. 
 
8. SAFETY MANAGEMENT 
 
Potential Risks 
 
 
The COSMOS-Mind procedures pose minimal risk to participants, which are primarily related to possible 
emotional discomfort related to cognitive testing and answering questions relating to self-perceptions of 
memory and mood. Participants could experience distress when learning that they may have a significant 
cognitive impairment, following adjudication by dementia experts.  COSMOS-Mind will only be contacting those 
with suspected dementia (i.e. not those with MCI), thus the letter will likely support preexisting suspicions 
regarding the participant’s cognitive status. 
 
Cognitive and Mood Assessment 
 
 
Examiners will be extensively trained to identify and appropriately respond to discomfort associated with 
cognitive testing, or questions about self-perceptions of memory or mood, including discontinuing the 
assessment, if necessary.  A study clinician experienced in the assessment and treatment of geriatric 
psychiatric disorders (Rapp) will contact participants who express suicidal ideation in the context of the mood 
assessment. Similar telephone-based testing protocols have been extensively used in other studies (e.g., 
WHIMS-ECHO, WHIMS-Y) with relatively fewer reports of participant discomfort in telephone-based versus 
face-to-face assessments. 
 
Disclosure Regarding Suspected Cognitive Impairment 
 
 
Participants with an adjudicated classification of probable dementia will receive a letter to alert them that 
the COSMOS-Mind test results suggest a significant cognitive impairment and to advise them to follow-up with 
their personal physician. A Release of Information form will be included with the letter with instructions to sign 
and return this form to the COSMOS-Mind team to request a summary of the results be sent to his/her primary 
care provider. The adjudication panel of dementia experts (Baker, Rapp, Sachs) will be available to these 

COSMOS-Mind Protocol, v05: 14Jun2017 
 
 
participants by telephone upon request. This disclosure protocol, developed for WHIMS has identified over 400 
cases of probable dementia since WHIMS was initiated. 
 
A ‘Cognitive Alert’ will be generated when an informant endorses items on the DQ that indicate impaired 
functional status (i.e.: ‘yes’ to any of Q1-Q6 ~AND~ ‘yes’ to any of Q14-16, Q18; ~OR~ answer to Q10 
indicates diagnosis of dementia or AD). When this occurs, members of the adjudication team (Baker, Rapp) 
will review the available test results to assess whether a classification of dementia is warranted. If so, the 
participant will receive the alert letter informing them of a possible cognitive impairment and to encourage 
follow-up. 
 
Protection against Risk 
 
 
The principles listed in the current edition of the Declaration of Helsinki will be implemented. Appropriate 
measures will be in place to protect against the risk of disclosing confidential information. The data will be 
collected for research purposes only. All paper records of the telephone assessment will be stored in locked 
cabinets in locked rooms, accessible only to the COSMOS-Mind investigators and staff.  Participants will be 
assigned a unique study identifier code on all study questionnaires and forms.  All electronic data – including 
the master list pairing participants’ names and codes, recordings of telephone assessments, personal health 
information, and study outcomes – will be stored in password-protected files on a secure network in a secured 
area. This network is protected with frequently updated anti-virus and anti-Trojan software, limited file sharing 
and file permissions to approved users only, and automated monitoring of access attempts. These procedures 
have successfully maintained security for many multicenter clinical trials. COSMOS-Mind will work with the 
COSMOS team at BWH to develop data transfer procedures and protocols using password protection and 
encryption, to permit seamless and secure exchange of information. Safety monitoring will be provided by the 
DSMB of the parent trial.  
 
Potential Benefits of the Proposed Research to Human Subjects and Others 
 
 
There is an urgent need to identify effective strategies to slow or prevent age-related cognitive decline.  
Although there may be no direct benefit to the participant for taking part in the study, COSMOS-Mind will 
provide a time- and cost-efficient assessment of whether a promising, safe, and widely translatable intervention 
can preserve cognitive function in older adults. 
 
Importance of the Knowledge to be Gained 
 
 
COSMOS-Mind will expand the scientific scope of the parent trial to include data about potential cognitive 
effects of the treatments that may reduce risk of cardiovascular disease and cancer in older adults. This 
intervention is inexpensive, easily accessible, and safe.  If daily use of high-potency cocoa flavanol extract, 
with or without a multivitamin, attenuate age-related cognitive decline and impairment, this research could have 
significant implications for standard of care to protect and preserve cognitive function in a fast-growing aging 
population in the US and worldwide. 
 
Data and Safety Monitoring Plan 
 
 
As an ancillary study to COSMOS, COSMOS-Mind will adhere to the reporting procedures to be 
established by the COSMOS DSMB. The COSMOS DSMB is expected to include representatives from the 
established VITAL and WHI DSMBs, together with additional experts in epidemiology, biostatistics, and other 
relevant clinical areas, including CVD and cancer. The possibility that an adverse event is reported during the 
telephone assessment is small; however, should this occur, staff will notify the COSMOS team to initiate their 
safety protocols. 
 
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