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| ID | Type | Description | Link |
|---|---|---|---|
| 1R01AG050657-01A1 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
| Brigham and Women's Hospital | OTHER |
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The parent trial (COcoa Supplement and Multivitamin Outcomes Study, COSMOS; NCT02422745) is a randomized clinical trial of cocoa extract supplement (containing a total of 500 mg/d flavanols, including 80 mg. (-)-epicatechins), and a standard multivitamin supplement to reduce the risk of cardiovascular disease and cancer among men aged 60 years and older and women aged 65 years and older. A cognitive ancillary study (COSMOS-Mind) is being conducted among men and women, 65 years and older, who are enrolled in COSMOS and will examine whether the cocoa extract supplement or the multivitamin supplement improves cognitive function and reduces risk of cognitive impairment, including Alzheimer's disease (AD) and other related types of dementia. Participants at the Wake Forest site will only be getting a phone call.
Identifying a safe, affordable, and well-tolerated intervention that prevents cognitive decline in older adults is of critical public health importance. There is compelling evidence from basic science, and small clinical studies that cocoa flavanols may protect cognitive function in older adults and reduce risk of Alzheimer's disease (AD) and related dementia. Thus, this intervention could have important downstream benefits for health care utilization and cost, caregiver burden, and overall quality of life for older adults. Cocoa flavanol effects on cognition, however, need to be assessed in a definitive clinical trial.
The parent trial (COSMOS) will enroll 21,442 women and men nationwide, drawn from the Women's Health Initiative (WHI) participant cohort and the VITamin D and OmegA-3 TriaL (VITAL) non-randomized respondent cohort, and will be conducted primarily by mail to assess whether high-potency cocoa flavanol extract and a multivitamin - alone or in combination - will reduce risk of cardiovascular disease and cancer over 3 years of follow-up.
After the COSMOS trial began, an advanced method to analyze cocoa flavanols was accredited by Association of Official Agricultural Chemists (AOAC) International as a First Action Official Method of Analysis https://doi.org/10.1093/jaoacint/qsaa132 [secure-web.cisco.com]). 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, this record 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.
Once participants are enrolled in COSMOS, the study team at Brigham and Women's Hospital will provide contact information and other parent trial outcomes for COSMOS-Mind participants to the Wake Forest 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).
COSMOS-Mind will only be administered a telephone cognitive assessment to all participants at enrollment (baseline), and annually for 3 years of follow-up by trained and certified staff of the Wake Forest COSMOS-Mind team.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Cocoa extract + multivitamin (MTV) | 2 capsules containing 500 mg/d cocoa extract; daily MTV | ||
| Cocoa extract + multivitamin placebo | 2 capsules containing 500 mg/d cocoa extract; daily MTV placebo | ||
| Cocoa extract placebo + multivitamin | Cocoa extract placebo (2 capsules/d); daily MTV | ||
| Cocoa extract placebo + multivitamin placebo | Cocoa extract placebo (2 capsules/d); daily MTV placebo |
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| Measure | Description | Time Frame |
|---|---|---|
| Global Cognitive Function: Average Change Over Follow-up From Baseline | A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The primary comparison is for the margins of the factorial design: active cocoa flavonal (with or without active multivitamin) versus placebo flavonal (with or without active multivitamin). | From Baseline through Year 3 |
| Measure | Description | Time Frame |
|---|---|---|
| Composite Cognitive Function | A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The comparison for this secondary outcome is based on the margins of the factorial design to compare multivitamin (with or without cocoa flavonal) with multivitamin placebo (with or without cocoa flavonal) |
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Participants in COSMOS (NCT02422745) who meet the following criteria are eligible to participate in this ancillary study:
Inclusion Criteria -
Exclusion Criteria -
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COSMOS-Mind will include 2,000 participants from the COSMOS parent trial who are at least 65 years of age, with approximately equal distribution of women and men.
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| Name | Affiliation | Role |
|---|---|---|
| Laura D Baker, PhD | Wake Forest University Health Sciences | Principal Investigator |
| Mark A Espeland, PhD | Wake Forest University Health Sciences | Principal Investigator |
| Stephen R Rapp, PhD | Co-Investigator Wake Forest School of Medicine | Principal Investigator |
| Sally A Shumaker, PhD | Co-Investigator Wake Forest School of Medicine | Principal Investigator |
| JoAnn E Manson, MD | Parent Study Principal Investigator/COSMOS Mind Co-Investigator Brigham and Women's Hospital | Principal Investigator |
| Howard Sesso, SCD, MPH | Parent Study Principal Investigator/COSMOS Mind Co-Investigator Brigham and Women's Hospital | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Wake Forest School of Medicine | Winston-Salem | North Carolina | 27157 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38244989 | Derived | Vyas CM, Manson JE, Sesso HD, Cook NR, Rist PM, Weinberg A, Moorthy MV, Baker LD, Espeland MA, Yeung LK, Brickman AM, Okereke OI. Effect of multivitamin-mineral supplementation versus placebo on cognitive function: results from the clinic subcohort of the COcoa Supplement and Multivitamin Outcomes Study (COSMOS) randomized clinical trial and meta-analysis of 3 cognitive studies within COSMOS. Am J Clin Nutr. 2024 Mar;119(3):692-701. doi: 10.1016/j.ajcnut.2023.12.011. Epub 2024 Jan 18. | |
| 31271875 |
| Label | URL |
|---|---|
| COcoa Supplement and Multivitamin Outcomes Study | View source |
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COSMOS-Mind and COSMOS (parent trial, PI: Manson and Sesso) have data transfer procedures and protocols in place which use password protection and encryption, to permit seamless and secure exchange of information. Safety monitoring will be completed through the parent trial. The COSMOS-Mind staff will send all adverse events reported to them to the parent trial for reporting and follow-up. This data will be sent electronically only to approved users through a protected network.
after completion of study
Data have been submitted to the parent COSMOS trial for merging with phenotypes and distribution.
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| ID | Title | Description |
|---|---|---|
| FG000 | Cocoa Extract + Multivitamin | Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver |
| FG001 | Cocoa Extract + Multivitamin Placebo | Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver placebo |
| FG002 | Cocoa Extract Placebo + Multivitamin | Daily cocoa extract placebo Daily Centrum Silver |
| FG003 | Cocoa Extract Placebo + Multivitamin Placebo | Daily cocoa extract placebo Daily Centrum Silver placebo |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Cocoa Extract + Multivitamin | Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver |
| BG001 | Cocoa Extract + Multivitamin Placebo |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Global Cognitive Function: Average Change Over Follow-up From Baseline | A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The primary comparison is for the margins of the factorial design: active cocoa flavonal (with or without active multivitamin) versus placebo flavonal (with or without active multivitamin). | Intention to treat -- All enrolled participants | Posted | Mean | Standard Error | score on a scale | From Baseline through Year 3 |
Across all follow-up -- 3 years.
Mortality was collected by the parent trial and passed on to us. Adverse events were collected and published by the parent COSMOS trial, but were not separately passed on to us. Per instructions from the reviewer, because mortality was not collected by COSMOS-Mind, we now do not report it in this document.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Cocoa Extract + Multivitamin | 2 capsules containing 500 mg/d cocoa extract; daily MTV |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Mark Espeland, PhD; Multiple Principal Investigator | Wake Forest University School of Medicine | 336-716-2826 | mespelan@wakehealth.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Jun 15, 2017 | Jun 14, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Apr 11, 2023 | Apr 13, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| D003704 | Dementia |
| D000544 | Alzheimer Disease |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D001927 | Brain Diseases |
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| From baseline through year 3 |
| Incident Mild Cognitive Impairment | Mild cognitive impairment based on centralized adjudication of cognitive test scores and input from a proxy. Limited to participants free of mild cognitive impairment at baseline. Incidence over 3 years of follow-up. | From baseline through year 3 |
| Incidence of Mild Cognitive Impairment Among Those Free at Baseline | Mild cognitive impairment based on central adjudication of test scores with input from proxies. Based on test scores administered annually across 3 years. | From baseline through year 3 |
| Executive Function | Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Linear contrast of scores collected at baseline, year 1, year 2, and year 3: (z1+z2+z3)/3 - z0) | From baseline through year 3 |
| Episodic Memory | Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. Annual test administrations. | From baseline through year 3 |
| Executive Function | Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Tests administered annually. | From baseline through year 3 |
| Episodic Memory | Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. | From baseline through year 3 |
| Baker LD, Rapp SR, Shumaker SA, Manson JE, Sesso HD, Gaussoin SA, Harris D, Caudle B, Pleasants D, Espeland MA; COSMOS-Mind Research Group. Design and baseline characteristics of the cocoa supplement and multivitamin outcomes study for the Mind: COSMOS-Mind. Contemp Clin Trials. 2019 Aug;83:57-63. doi: 10.1016/j.cct.2019.06.019. Epub 2019 Jul 2. |
| Withdrawal by Subject |
|
| Lost to Follow-up |
|
Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver placebo
| BG002 | Cocoa Extract Placebo + Multivitamin | Daily cocoa extract placebo Daily Centrum Silver |
| BG003 | Cocoa Extract Placebo + Multivitamin Placebo | Daily cocoa extract placebo Daily Centrum Silver placebo |
| BG004 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Global Cognitive Composite | The global composite is average of z-scores for each component. Each component has mean 0 at baseline, thus the composite z-score has mean 0. Individual component tests are 1) Telephone Interview for Cognitive Status-modified that measures global cognitive function, 2) Immediate and Delayed Story Recall tests for verbal memory, 3) Oral Trail Making Test for attention and executive function, 4) Verbal Fluency, 5) Number Span Test for attention and working memory, and 5) Digit Ordering Test for working memory. Higher positive scores reflect better performance. There are no clinical thresholds. | Mean | Standard Deviation | z-scores |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | Cocoa Extract + Multivitamin | 2 capsules containing 500 mg/d cocoa extract; daily MTV |
| OG001 | Cocoa Extract + Multivitamin Placebo | 2 capsules containing 500 mg/d cocoa extract; daily MTV placebo |
| OG002 | Cocoa Extract Placebo + Multivitamin | Cocoa extract placebo (2 capsules/d); daily MTV |
| OG003 | Cocoa Extract Placebo + Multivitamin Placebo | Cocoa extract placebo (2 capsules/d); daily MTV placebo |
|
|
|
| Secondary | Composite Cognitive Function | A composite cognitive measure that averages individual test z-scores of the Telephone Interview for Cognitive Status-modified (TICSm) Total and Long, the Immediate and Delayed Story Recall tests, the Oral Trail Making A and B tests (log-transformed), the Category Fluency and Verbal Fluency tests, and the Number Span Backward and Forward tests. Scores are ordered so that better performance corresponds to higher positive scores. Longitudinal data are used to create a linear contrast for the primary analysis to compare the difference between the average of scores at Years 1, 2, and 3 and the baseline score, i.e. (z1+z2+z3)/3 - z0, where z's denote the composited measures at baseline and years 1-3. This contrast is fitted using a random effects model for repeated measures. The comparison for this secondary outcome is based on the margins of the factorial design to compare multivitamin (with or without cocoa flavonal) with multivitamin placebo (with or without cocoa flavonal) | Complete randomized cohort | Posted | Least Squares Mean | Standard Error | score on a scale | From baseline through year 3 |
|
|
|
|
| Secondary | Incident Mild Cognitive Impairment | Mild cognitive impairment based on centralized adjudication of cognitive test scores and input from a proxy. Limited to participants free of mild cognitive impairment at baseline. Incidence over 3 years of follow-up. | Limited to participants free of mild cognitive impairment at baseline. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan. | Posted | Count of Participants | Participants | From baseline through year 3 |
|
|
|
|
| Secondary | Incidence of Mild Cognitive Impairment Among Those Free at Baseline | Mild cognitive impairment based on central adjudication of test scores with input from proxies. Based on test scores administered annually across 3 years. | Participants free of mild cognitive impairment at baseline. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan. | Posted | Count of Participants | Participants | From baseline through year 3 |
|
|
|
|
| Secondary | Executive Function | Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Linear contrast of scores collected at baseline, year 1, year 2, and year 3: (z1+z2+z3)/3 - z0) | All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan. | Posted | Least Squares Mean | Standard Error | score on a scale | From baseline through year 3 |
|
|
|
|
| Secondary | Episodic Memory | Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. Annual test administrations. | In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan. | Posted | Least Squares Mean | Standard Error | score on a scale | From baseline through year 3 |
|
|
|
|
| Secondary | Executive Function | Average of z-scores for the following tests: Oral Trail Making Test - B (log-transformed), Category Verbal Fluency, Letter Verbal Fluency, Number Span Test (Backwards and Forward). Higher (positive) scores reflect better performance. Tests administered annually. | All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan. | Posted | Least Squares Mean | Standard Error | score on a scale | From baseline through year 3 |
|
|
|
|
| Secondary | Episodic Memory | Average z-scores from Telephone Interview for Cognitive Status-modified Delayed Word List, Story Immediate Recall, Story Delayed Recall. Higher (positive) scores reflect better performance. | All randomized participants. In a factorial design such as this, primary comparisons are cocoa flavanol vs cocoa flavanol placebo (pooling across multivitamin and multivitamin placebo) and multivitamin vs multivitamin placebo (pooling across cocoa flavanol and cocoa flavanol placebo). To provide outcomes for the four cells does not conform with the protocol or the published results and will not be consistent with the statistical analysis plan. | Posted | Least Squares Mean | Standard Error | score on a scale | From baseline through year 3 |
|
|
|
|
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | Cocoa Extract + Multivitamin Placebo | 2 capsules containing 500 mg/d cocoa extract; daily MTV placebo | 0 | 0 | 0 | 0 | 0 | 0 |
| EG002 | Cocoa Extract Placebo + Multivitamin | Cocoa extract placebo (2 capsules/d); daily MTV | 0 | 0 | 0 | 0 | 0 | 0 |
| EG003 | Cocoa Extract Placebo + Multivitamin Placebo | Cocoa extract placebo (2 capsules/d); daily MTV placebo | 0 | 0 | 0 | 0 | 0 | 0 |
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| D002493 |
| Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
| D024801 | Tauopathies |
| D019636 | Neurodegenerative Diseases |
Wald test of a linear contrast from the mixed effects analysis....see protocol |