Trial Outcomes & Findings for COcoa Supplement and Multivitamin Outcomes Study for the Mind (NCT NCT03035201)
NCT ID: NCT03035201
Last Updated: 2023-08-22
Results Overview
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).
COMPLETED
2262 participants
From Baseline through Year 3
2023-08-22
Participant Flow
Participant milestones
| Measure |
Cocoa Extract + Multivitamin
Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver
|
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
|
Cocoa Extract Placebo + Multivitamin
Daily cocoa extract placebo Daily Centrum Silver
|
Cocoa Extract Placebo + Multivitamin Placebo
Daily cocoa extract placebo Daily Centrum Silver placebo
|
|---|---|---|---|---|
|
Overall Study
STARTED
|
571
|
553
|
551
|
587
|
|
Overall Study
COMPLETED
|
444
|
441
|
441
|
462
|
|
Overall Study
NOT COMPLETED
|
127
|
112
|
110
|
125
|
Reasons for withdrawal
| Measure |
Cocoa Extract + Multivitamin
Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver
|
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
|
Cocoa Extract Placebo + Multivitamin
Daily cocoa extract placebo Daily Centrum Silver
|
Cocoa Extract Placebo + Multivitamin Placebo
Daily cocoa extract placebo Daily Centrum Silver placebo
|
|---|---|---|---|---|
|
Overall Study
Death
|
9
|
12
|
9
|
10
|
|
Overall Study
Withdrawal by Subject
|
51
|
49
|
37
|
46
|
|
Overall Study
Lost to Follow-up
|
67
|
51
|
64
|
69
|
Baseline Characteristics
COcoa Supplement and Multivitamin Outcomes Study for the Mind
Baseline characteristics by cohort
| Measure |
Cocoa Extract + Multivitamin
n=571 Participants
Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver
|
Cocoa Extract + Multivitamin Placebo
n=553 Participants
Daily cocoa extract (capsule containing 750 mg/d flavanols, including 75 mg (-)-epicatechin, and 90 mg theobromine) Daily Centrum Silver placebo
|
Cocoa Extract Placebo + Multivitamin
n=551 Participants
Daily cocoa extract placebo Daily Centrum Silver
|
Cocoa Extract Placebo + Multivitamin Placebo
n=587 Participants
Daily cocoa extract placebo Daily Centrum Silver placebo
|
Total
n=2262 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Continuous
|
72.7 years
STANDARD_DEVIATION 5.5 • n=93 Participants
|
73.2 years
STANDARD_DEVIATION 5.6 • n=4 Participants
|
72.9 years
STANDARD_DEVIATION 5.6 • n=27 Participants
|
73.1 years
STANDARD_DEVIATION 5.7 • n=483 Participants
|
73.0 years
STANDARD_DEVIATION 5.6 • n=36 Participants
|
|
Sex: Female, Male
Female
|
339 Participants
n=93 Participants
|
330 Participants
n=4 Participants
|
319 Participants
n=27 Participants
|
360 Participants
n=483 Participants
|
1348 Participants
n=36 Participants
|
|
Sex: Female, Male
Male
|
232 Participants
n=93 Participants
|
223 Participants
n=4 Participants
|
232 Participants
n=27 Participants
|
227 Participants
n=483 Participants
|
914 Participants
n=36 Participants
|
|
Race/Ethnicity, Customized
American Indian/Alaska Native
|
2 Participants
n=93 Participants
|
1 Participants
n=4 Participants
|
8 Participants
n=27 Participants
|
2 Participants
n=483 Participants
|
13 Participants
n=36 Participants
|
|
Race/Ethnicity, Customized
Asian/Pacific Islander
|
9 Participants
n=93 Participants
|
12 Participants
n=4 Participants
|
10 Participants
n=27 Participants
|
8 Participants
n=483 Participants
|
39 Participants
n=36 Participants
|
|
Race/Ethnicity, Customized
Black/African American
|
40 Participants
n=93 Participants
|
23 Participants
n=4 Participants
|
34 Participants
n=27 Participants
|
34 Participants
n=483 Participants
|
131 Participants
n=36 Participants
|
|
Race/Ethnicity, Customized
Hispanic
|
13 Participants
n=93 Participants
|
18 Participants
n=4 Participants
|
15 Participants
n=27 Participants
|
21 Participants
n=483 Participants
|
67 Participants
n=36 Participants
|
|
Race/Ethnicity, Customized
Multiracial/Unknown
|
1 Participants
n=93 Participants
|
1 Participants
n=4 Participants
|
2 Participants
n=27 Participants
|
2 Participants
n=483 Participants
|
6 Participants
n=36 Participants
|
|
Race/Ethnicity, Customized
Non-Hispanic White
|
506 Participants
n=93 Participants
|
498 Participants
n=4 Participants
|
482 Participants
n=27 Participants
|
520 Participants
n=483 Participants
|
2006 Participants
n=36 Participants
|
|
Region of Enrollment
United States
|
571 participants
n=93 Participants
|
553 participants
n=4 Participants
|
551 participants
n=27 Participants
|
587 participants
n=483 Participants
|
2262 participants
n=36 Participants
|
|
Global Cognitive Composite
|
-0.01 z-scores
STANDARD_DEVIATION 0.99 • n=93 Participants
|
0.02 z-scores
STANDARD_DEVIATION 1.00 • n=4 Participants
|
0.05 z-scores
STANDARD_DEVIATION 1.02 • n=27 Participants
|
-0.05 z-scores
STANDARD_DEVIATION 0.99 • n=483 Participants
|
0.00 z-scores
STANDARD_DEVIATION 1.00 • n=36 Participants
|
PRIMARY outcome
Timeframe: From Baseline through Year 3Population: Intention to treat -- All enrolled participants
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).
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=571 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=553 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV placebo
|
Cocoa Extract Placebo + Multivitamin
n=551 Participants
Cocoa extract placebo (2 capsules/d); daily MTV
|
Cocoa Extract Placebo + Multivitamin Placebo
n=587 Participants
Cocoa extract placebo (2 capsules/d); daily MTV placebo
|
|---|---|---|---|---|
|
Global Cognitive Function: Average Change Over Follow-up From Baseline
|
0.24 score on a scale
Standard Error 0.02
|
0.15 score on a scale
Standard Error 0.02
|
0.20 score on a scale
Standard Error 0.02
|
0.15 score on a scale
Standard Error 0.02
|
SECONDARY outcome
Timeframe: From baseline through year 3Population: Complete randomized cohort
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)
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=571 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=553 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV placebo
|
Cocoa Extract Placebo + Multivitamin
n=551 Participants
Cocoa extract placebo (2 capsules/d); daily MTV
|
Cocoa Extract Placebo + Multivitamin Placebo
n=587 Participants
Cocoa extract placebo (2 capsules/d); daily MTV placebo
|
|---|---|---|---|---|
|
Composite Cognitive Function
|
0.24 score on a scale
Standard Error 0.02
|
0.15 score on a scale
Standard Error 0.02
|
0.20 score on a scale
Standard Error 0.02
|
0.15 score on a scale
Standard Error 0.02
|
SECONDARY outcome
Timeframe: From baseline through year 3Population: 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.
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.
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=916 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=940 Participants
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
|
|---|---|---|---|---|
|
Incident Mild Cognitive Impairment
|
47 Participants
|
63 Participants
|
—
|
—
|
SECONDARY outcome
Timeframe: From baseline through year 3Population: 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.
Mild cognitive impairment based on central adjudication of test scores with input from proxies. Based on test scores administered annually across 3 years.
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=920 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=936 Participants
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
|
|---|---|---|---|---|
|
Incidence of Mild Cognitive Impairment Among Those Free at Baseline
|
53 Participants
|
57 Participants
|
—
|
—
|
SECONDARY outcome
Timeframe: From baseline through year 3Population: 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.
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)
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=1144 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=1138 Participants
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
|
|---|---|---|---|---|
|
Executive Function
|
0.06 score on a scale
Standard Error 0.02
|
0.04 score on a scale
Standard Error 0.02
|
—
|
—
|
SECONDARY outcome
Timeframe: From baseline through year 3Population: 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.
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.
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=1144 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=1138 Participants
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
|
|---|---|---|---|---|
|
Episodic Memory
|
0.29 score on a scale
Standard Error 0.02
|
0.27 score on a scale
Standard Error 0.02
|
—
|
—
|
SECONDARY outcome
Timeframe: From baseline through year 3Population: 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.
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.
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=1128 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=1140 Participants
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
|
|---|---|---|---|---|
|
Executive Function
|
0.08 score on a scale
Standard Error 0.02
|
0.02 score on a scale
Standard Error 0.02
|
—
|
—
|
SECONDARY outcome
Timeframe: From baseline through year 3Population: 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.
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.
Outcome measures
| Measure |
Cocoa Extract + Multivitamin
n=1128 Participants
2 capsules containing 500 mg/d cocoa extract; daily MTV
|
Cocoa Extract + Multivitamin Placebo
n=1140 Participants
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
|
|---|---|---|---|---|
|
Episodic Memory
|
0.31 score on a scale
Standard Error 0.02
|
0.25 score on a scale
Standard Error 0.02
|
—
|
—
|
Adverse Events
Cocoa Extract + Multivitamin
Cocoa Extract + Multivitamin Placebo
Cocoa Extract Placebo + Multivitamin
Cocoa Extract Placebo + Multivitamin Placebo
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Mark Espeland, PhD; Multiple Principal Investigator
Wake Forest University School of Medicine
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place