Trial Outcomes & Findings for COcoa Supplement and Multivitamin Outcomes Study (NCT NCT02422745)
NCT ID: NCT02422745
Last Updated: 2025-09-24
Results Overview
CVD events include myocardial infarction, stroke, cardiovascular deaths, coronary revascularization procedures, unstable angina or acute coronary syndrome (ACS) requiring hospitalization, carotid artery surgery, and peripheral artery surgery or angioplasty. CVD events are confirmed by review of discharge summaries, ECG's, laboratory reports, test reports, radiology reports, surgical reports, medical records for reports of increased pain, use of medication to alleviate pain, and evidence of troponin leak, and death certificates.
Recruitment status
COMPLETED
Study phase
PHASE4
Target enrollment
21442 participants
Primary outcome timeframe
4 years
Results posted on
2025-09-24
Participant Flow
191769 initially screened; 35669 eligible to enter run-in; 21442 eligible for randomization; 2x2 factorial design; 10719 assigned to active cocoa extract (of these, 5360 were assigned to active multivitamin and 5359 to placebo multivitamin) \& 10723 assigned to placebo cocoa extract (of these, 5360 were assigned to active multivitamin and 5363 to placebo multivitamin)
The trial included at least a 2-month placebo run-in period to select participants likely to have excellent compliance. Only individuals who reported taking at least 75% or more of their their study pills during the run-in and met other eligibility criteria were randomized into the trial.
Participant milestones
| Measure |
ACTIVE Cocoa Extract + ACTIVE Multivitamin
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin, and 50 mg theobromine
Multivitamin: Multivitamin
|
ACTIVE Cocoa Extract + PLACEBO Multivitamin
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin, and 50 mg theobromine
Multivitamin placebo: Multivitamin placebo
|
PLACEBO Cocoa Extract + ACTIVE Multivitamin
Multivitamin: Multivitamin
Cocoa extract placebo: Cocoa extract placebo
|
PLACEBO Cocoa Extract + PLACEBO Multivitamin
Cocoa extract placebo: Cocoa extract placebo
Multivitamin placebo: Multivitamin placebo
|
|---|---|---|---|---|
|
Overall Study
STARTED
|
5360
|
5359
|
5360
|
5363
|
|
Overall Study
COMPLETED
|
5360
|
5359
|
5360
|
5363
|
|
Overall Study
NOT COMPLETED
|
0
|
0
|
0
|
0
|
Reasons for withdrawal
Withdrawal data not reported
Baseline Characteristics
COcoa Supplement and Multivitamin Outcomes Study
Baseline characteristics by cohort
| Measure |
ACTIVE Cocoa Extract + ACTIVE Multivitamin
n=5360 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
Multivitamin: Multivitamin
|
ACTIVE Cocoa Extract + PLACEBO Multivitamin
n=5359 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
Multivitamin placebo: Multivitamin placebo
|
PLACEBO Cocoa Extract + ACTIVE Multivitamin
n=5360 Participants
Multivitamin: Multivitamin
Cocoa extract placebo: Cocoa extract placebo
|
PLACEBO Cocoa Extract + PLACEBO Multivitamin
n=5363 Participants
Cocoa extract placebo: Cocoa extract placebo
Multivitamin placebo: Multivitamin placebo
|
Total
n=21442 Participants
Total of all reporting groups
|
|---|---|---|---|---|---|
|
Age, Categorical
<=18 years
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
0 Participants
n=4 Participants
|
0 Participants
n=21 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
675 Participants
n=5 Participants
|
676 Participants
n=7 Participants
|
676 Participants
n=5 Participants
|
678 Participants
n=4 Participants
|
2705 Participants
n=21 Participants
|
|
Age, Categorical
>=65 years
|
4685 Participants
n=5 Participants
|
4683 Participants
n=7 Participants
|
4684 Participants
n=5 Participants
|
4685 Participants
n=4 Participants
|
18737 Participants
n=21 Participants
|
|
Age, Continuous
|
72.1 years
STANDARD_DEVIATION 6.6 • n=5 Participants
|
72.1 years
STANDARD_DEVIATION 6.6 • n=7 Participants
|
72.1 years
STANDARD_DEVIATION 6.5 • n=5 Participants
|
72.1 years
STANDARD_DEVIATION 6.5 • n=4 Participants
|
72.1 years
STANDARD_DEVIATION 6.6 • n=21 Participants
|
|
Sex: Female, Male
Female
|
3171 Participants
n=5 Participants
|
3166 Participants
n=7 Participants
|
3167 Participants
n=5 Participants
|
3162 Participants
n=4 Participants
|
12666 Participants
n=21 Participants
|
|
Sex: Female, Male
Male
|
2189 Participants
n=5 Participants
|
2193 Participants
n=7 Participants
|
2193 Participants
n=5 Participants
|
2201 Participants
n=4 Participants
|
8776 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
White
|
4796 Participants
n=5 Participants
|
4828 Participants
n=7 Participants
|
4832 Participants
n=5 Participants
|
4838 Participants
n=4 Participants
|
19294 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Black
|
290 Participants
n=5 Participants
|
268 Participants
n=7 Participants
|
278 Participants
n=5 Participants
|
295 Participants
n=4 Participants
|
1131 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Asian/Pacific Islander
|
138 Participants
n=5 Participants
|
136 Participants
n=7 Participants
|
120 Participants
n=5 Participants
|
105 Participants
n=4 Participants
|
499 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
American Indian/Alaskan Native
|
17 Participants
n=5 Participants
|
14 Participants
n=7 Participants
|
20 Participants
n=5 Participants
|
8 Participants
n=4 Participants
|
59 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Multiracial/other/unknown or not reported
|
119 Participants
n=5 Participants
|
113 Participants
n=7 Participants
|
110 Participants
n=5 Participants
|
117 Participants
n=4 Participants
|
459 Participants
n=21 Participants
|
|
Race/Ethnicity, Customized
Hispanic/Latino
|
134 Participants
n=5 Participants
|
118 Participants
n=7 Participants
|
150 Participants
n=5 Participants
|
142 Participants
n=4 Participants
|
544 Participants
n=21 Participants
|
|
Region of Enrollment
United States
|
5360 participants
n=5 Participants
|
5359 participants
n=7 Participants
|
5360 participants
n=5 Participants
|
5363 participants
n=4 Participants
|
21442 participants
n=21 Participants
|
|
Education
High school diploma/GED or less
|
588 Participants
n=5 Participants
|
553 Participants
n=7 Participants
|
592 Participants
n=5 Participants
|
563 Participants
n=4 Participants
|
2296 Participants
n=21 Participants
|
|
Education
Attended or graduated from college
|
2117 Participants
n=5 Participants
|
2211 Participants
n=7 Participants
|
2198 Participants
n=5 Participants
|
2159 Participants
n=4 Participants
|
8685 Participants
n=21 Participants
|
|
Education
Post-college
|
2596 Participants
n=5 Participants
|
2551 Participants
n=7 Participants
|
2508 Participants
n=5 Participants
|
2586 Participants
n=4 Participants
|
10241 Participants
n=21 Participants
|
|
Body mass index (BMI)
|
27.6 kg/m2
STANDARD_DEVIATION 5.3 • n=5 Participants
|
27.7 kg/m2
STANDARD_DEVIATION 5.4 • n=7 Participants
|
27.7 kg/m2
STANDARD_DEVIATION 5.4 • n=5 Participants
|
27.8 kg/m2
STANDARD_DEVIATION 5.5 • n=4 Participants
|
27.7 kg/m2
STANDARD_DEVIATION 5.4 • n=21 Participants
|
|
Cocoa extract use before run-in
|
22 Participants
n=5 Participants
|
23 Participants
n=7 Participants
|
20 Participants
n=5 Participants
|
26 Participants
n=4 Participants
|
91 Participants
n=21 Participants
|
|
Multivitamin use before run-in
|
2237 Participants
n=5 Participants
|
2201 Participants
n=7 Participants
|
2176 Participants
n=5 Participants
|
2181 Participants
n=4 Participants
|
8795 Participants
n=21 Participants
|
|
Chocolate intake
Rarely
|
850 Participants
n=5 Participants
|
790 Participants
n=7 Participants
|
850 Participants
n=5 Participants
|
862 Participants
n=4 Participants
|
3352 Participants
n=21 Participants
|
|
Chocolate intake
Monthly
|
716 Participants
n=5 Participants
|
739 Participants
n=7 Participants
|
751 Participants
n=5 Participants
|
717 Participants
n=4 Participants
|
2923 Participants
n=21 Participants
|
|
Chocolate intake
Weekly
|
2800 Participants
n=5 Participants
|
2806 Participants
n=7 Participants
|
2775 Participants
n=5 Participants
|
2748 Participants
n=4 Participants
|
11129 Participants
n=21 Participants
|
|
Chocolate intake
At least daily
|
568 Participants
n=5 Participants
|
566 Participants
n=7 Participants
|
586 Participants
n=5 Participants
|
597 Participants
n=4 Participants
|
2317 Participants
n=21 Participants
|
|
History of cardiovascular disease
|
336 Participants
n=5 Participants
|
290 Participants
n=7 Participants
|
307 Participants
n=5 Participants
|
336 Participants
n=4 Participants
|
1269 Participants
n=21 Participants
|
|
Personal history of cancer
|
917 Participants
n=5 Participants
|
858 Participants
n=7 Participants
|
896 Participants
n=5 Participants
|
879 Participants
n=4 Participants
|
3550 Participants
n=21 Participants
|
|
History of diabetes
|
702 Participants
n=5 Participants
|
715 Participants
n=7 Participants
|
713 Participants
n=5 Participants
|
734 Participants
n=4 Participants
|
2864 Participants
n=21 Participants
|
|
History of hypertension
|
3048 Participants
n=5 Participants
|
3142 Participants
n=7 Participants
|
3105 Participants
n=5 Participants
|
3128 Participants
n=4 Participants
|
12423 Participants
n=21 Participants
|
|
Cholesterol-lowering medication use
|
2366 Participants
n=5 Participants
|
2346 Participants
n=7 Participants
|
2348 Participants
n=5 Participants
|
2345 Participants
n=4 Participants
|
9405 Participants
n=21 Participants
|
|
Aspirin use in past month
|
2617 Participants
n=5 Participants
|
2594 Participants
n=7 Participants
|
2551 Participants
n=5 Participants
|
2617 Participants
n=4 Participants
|
10379 Participants
n=21 Participants
|
|
Smoking status
Current
|
199 Participants
n=5 Participants
|
199 Participants
n=7 Participants
|
218 Participants
n=5 Participants
|
219 Participants
n=4 Participants
|
835 Participants
n=21 Participants
|
|
Smoking status
Past
|
2173 Participants
n=5 Participants
|
2223 Participants
n=7 Participants
|
2172 Participants
n=5 Participants
|
2163 Participants
n=4 Participants
|
8731 Participants
n=21 Participants
|
|
Smoking status
Never
|
2904 Participants
n=5 Participants
|
2862 Participants
n=7 Participants
|
2904 Participants
n=5 Participants
|
2895 Participants
n=4 Participants
|
11565 Participants
n=21 Participants
|
PRIMARY outcome
Timeframe: 4 yearsCVD events include myocardial infarction, stroke, cardiovascular deaths, coronary revascularization procedures, unstable angina or acute coronary syndrome (ACS) requiring hospitalization, carotid artery surgery, and peripheral artery surgery or angioplasty. CVD events are confirmed by review of discharge summaries, ECG's, laboratory reports, test reports, radiology reports, surgical reports, medical records for reports of increased pain, use of medication to alleviate pain, and evidence of troponin leak, and death certificates.
Outcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Total Cardiovascular Disease (CVD) Events
|
410 Participants
|
456 Participants
|
429 Participants
|
437 Participants
|
PRIMARY outcome
Timeframe: 4 yearsDiagnoses of invasive cancer are confirmed by review of discharge summaries, pathology reports, operative reports, surgical reports, and diagnostic or treatment procedure reports, including both inpatient and outpatient procedures.
Outcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Invasive Cancer Events
|
550 Participants
|
503 Participants
|
518 Participants
|
535 Participants
|
SECONDARY outcome
Timeframe: 4 yearsThis outcome was a composite of myocardial infarction, stroke, cardiovascular deaths, and coronary revascularization procedures.
Outcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Composite Endpoint of MI, Stroke, Cardiovascular Mortality, and Coronary Revascularization
|
362 Participants
|
403 Participants
|
381 Participants
|
384 Participants
|
SECONDARY outcome
Timeframe: 4 yearsThis outcome was a composite of myocardial infarction, stroke, cardiovascular deaths, coronary revascularization procedures, unstable angina or acute coronary syndrome (ACS) requiring hospitalization, carotid artery surgery, and peripheral artery surgery or angioplasty, plus all-cause mortality.
Outcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Total Cardiovascular Events Plus All-Cause Mortality
|
665 Participants
|
731 Participants
|
680 Participants
|
716 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Myocardial Infarction
|
88 Participants
|
101 Participants
|
96 Participants
|
93 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Stroke
|
113 Participants
|
124 Participants
|
121 Participants
|
116 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Cardiovascular Mortality
|
76 Participants
|
104 Participants
|
84 Participants
|
96 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Coronary Revascularization
|
166 Participants
|
175 Participants
|
177 Participants
|
164 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Unstable Angina or Acute Coronary Syndrome Requiring Hospitalization
|
46 Participants
|
46 Participants
|
50 Participants
|
42 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Carotid Artery Surgery
|
25 Participants
|
27 Participants
|
24 Participants
|
28 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Peripheral Artery Surgery or Angioplasty
|
17 Participants
|
19 Participants
|
16 Participants
|
20 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Total Mortality
|
353 Participants
|
397 Participants
|
362 Participants
|
388 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Breast Cancer
|
99 Participants
|
81 Participants
|
93 Participants
|
87 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Colorectal Cancer
|
38 Participants
|
29 Participants
|
38 Participants
|
29 Participants
|
SECONDARY outcome
Timeframe: 4 yearsOutcome measures
| Measure |
Active Cocoa Extract
n=10719 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=10723 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=10722 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Number of Participants With Lung Cancer
|
49 Participants
|
58 Participants
|
41 Participants
|
66 Participants
|
SECONDARY outcome
Timeframe: 2 yearsPopulation: Within the subcohort providing a baseline and follow-up biospecimen, gVLM levels were analyzed from spot urine samples collected from 1,917 participants at 2 years follow-up.
Baseline biospecimens were obtained during the run-in period from 6867 (32.0%) of 21,442 randomized participants, of whom 2050 participants comprised a longitudinal subcohort providing a baseline and at least one follow-up blood and/or spot urine sample at 1, 2, and/or 3 years follow-up. This includes 1,917 participants specifically providing spot urine samples at baseline and Year 2. From the spot urine samples collected, habitual flavanol consumption was estimated by urinary concentrations of 5-(3',4'-dihydroxyphenyl)-γ-valerolactone metabolite (gVLM), which are a biomarker of flavanol intake.
Outcome measures
| Measure |
Active Cocoa Extract
n=992 Participants
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Cocoa Extract Placebo
n=925 Participants
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=966 Participants
Multivitamin, 1 tablet/day
|
Multivitamin Placebo
n=951 Participants
Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|
|
Median Urinary gVLM Levels at Year 2 Among Those Providing Spot Urine at Baseline and Year 2
|
10.3 μM
Interval 2.1 to 36.9
|
2.9 μM
Interval 0.7 to 10.2
|
5.9 μM
Interval 1.2 to 22.3
|
5.3 μM
Interval 1.2 to 19.6
|
OTHER_PRE_SPECIFIED outcome
Timeframe: 2 yearsOutcome measures
Outcome data not reported
OTHER_PRE_SPECIFIED outcome
Timeframe: 2 yearsAssessed by pulse wave analysis
Outcome measures
Outcome data not reported
OTHER_PRE_SPECIFIED outcome
Timeframe: 2 yearsBalance tests, grip strength, timed chair stands, walking speed
Outcome measures
Outcome data not reported
OTHER_PRE_SPECIFIED outcome
Timeframe: 2 yearsAssessed by dual x-ray absorptiometry
Outcome measures
Outcome data not reported
OTHER_PRE_SPECIFIED outcome
Timeframe: 2 yearsOutcome measures
Outcome data not reported
Adverse Events
Active Cocoa Extract
Serious events: 1378 serious events
Other events: 9965 other events
Deaths: 353 deaths
Placebo Cocoa Extract
Serious events: 1372 serious events
Other events: 9950 other events
Deaths: 397 deaths
Active Multivitamin
Serious events: 1388 serious events
Other events: 9942 other events
Deaths: 362 deaths
Placebo Multivitamin
Serious events: 1362 serious events
Other events: 9973 other events
Deaths: 388 deaths
Active Cocoa Extract + Active Multivitamin
Serious events: 703 serious events
Other events: 4985 other events
Deaths: 175 deaths
Active Cocoa Extract + Placebo Multivitamin
Serious events: 675 serious events
Other events: 4980 other events
Deaths: 178 deaths
Placebo Cocoa Extract + Active Multivitamin
Serious events: 685 serious events
Other events: 4957 other events
Deaths: 187 deaths
Placebo Cocoa Extract + Placebo Multivitamin
Serious events: 687 serious events
Other events: 4993 other events
Deaths: 210 deaths
Serious adverse events
| Measure |
Active Cocoa Extract
n=10719 participants at risk
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Placebo Cocoa Extract
n=10723 participants at risk
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 participants at risk
Multivitamin, 1 tablet/day
|
Placebo Multivitamin
n=10722 participants at risk
Multivitamin placebo, 1 tablet/day
|
Active Cocoa Extract + Active Multivitamin
n=5360 participants at risk
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
Multivitamin: Multivitamin, 1 tablet/day
|
Active Cocoa Extract + Placebo Multivitamin
n=5359 participants at risk
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
Multivitamin placebo: Multivitamin placebo, 1 tablet/day
|
Placebo Cocoa Extract + Active Multivitamin
n=5360 participants at risk
Multivitamin: Multivitamin, 1 tablet/day
Cocoa extract placebo: Cocoa extract placebo, 2 capsules/day
|
Placebo Cocoa Extract + Placebo Multivitamin
n=5363 participants at risk
Cocoa extract placebo: Cocoa extract placebo, 2 capsules/day
Multivitamin placebo: Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|---|---|---|---|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Colorectal cancer
|
0.35%
38/10719 • 4 years
|
0.27%
29/10723 • 4 years
|
0.35%
38/10720 • 4 years
|
0.27%
29/10722 • 4 years
|
0.41%
22/5360 • 4 years
|
0.30%
16/5359 • 4 years
|
0.30%
16/5360 • 4 years
|
0.24%
13/5363 • 4 years
|
|
Vascular disorders
Total cardiovascular event
|
3.8%
410/10719 • 4 years
|
4.3%
456/10723 • 4 years
|
4.0%
429/10720 • 4 years
|
4.1%
437/10722 • 4 years
|
3.8%
206/5360 • 4 years
|
3.8%
204/5359 • 4 years
|
4.2%
223/5360 • 4 years
|
4.3%
233/5363 • 4 years
|
|
Vascular disorders
Major cardiovascular event plus CABG/PCI
|
3.4%
362/10719 • 4 years
|
3.8%
403/10723 • 4 years
|
3.6%
381/10720 • 4 years
|
3.6%
384/10722 • 4 years
|
3.4%
180/5360 • 4 years
|
3.4%
182/5359 • 4 years
|
3.8%
201/5360 • 4 years
|
3.8%
202/5363 • 4 years
|
|
Vascular disorders
Myocardial infarction
|
0.82%
88/10719 • 4 years
|
0.94%
101/10723 • 4 years
|
0.90%
96/10720 • 4 years
|
0.87%
93/10722 • 4 years
|
0.88%
47/5360 • 4 years
|
0.77%
41/5359 • 4 years
|
0.91%
49/5360 • 4 years
|
0.97%
52/5363 • 4 years
|
|
Vascular disorders
Stroke
|
1.1%
113/10719 • 4 years
|
1.2%
124/10723 • 4 years
|
1.1%
121/10720 • 4 years
|
1.1%
116/10722 • 4 years
|
1.0%
56/5360 • 4 years
|
1.1%
57/5359 • 4 years
|
1.2%
65/5360 • 4 years
|
1.1%
59/5363 • 4 years
|
|
Vascular disorders
Death from cardiovascular causes
|
0.71%
76/10719 • 4 years
|
0.97%
104/10723 • 4 years
|
0.78%
84/10720 • 4 years
|
0.90%
96/10722 • 4 years
|
0.69%
37/5360 • 4 years
|
0.73%
39/5359 • 4 years
|
0.88%
47/5360 • 4 years
|
1.1%
57/5363 • 4 years
|
|
Vascular disorders
Coronary revascularization procedures
|
1.5%
166/10719 • 4 years
|
1.6%
175/10723 • 4 years
|
1.7%
177/10720 • 4 years
|
1.5%
164/10722 • 4 years
|
1.6%
87/5360 • 4 years
|
1.5%
79/5359 • 4 years
|
1.7%
90/5360 • 4 years
|
1.6%
85/5363 • 4 years
|
|
Vascular disorders
Unstable angina requiring hospitalization
|
0.43%
46/10719 • 4 years
|
0.43%
46/10723 • 4 years
|
0.47%
50/10720 • 4 years
|
0.39%
42/10722 • 4 years
|
0.49%
26/5360 • 4 years
|
0.37%
20/5359 • 4 years
|
0.45%
24/5360 • 4 years
|
0.41%
22/5363 • 4 years
|
|
Vascular disorders
Carotid artery disease
|
0.23%
25/10719 • 4 years
|
0.25%
27/10723 • 4 years
|
0.22%
24/10720 • 4 years
|
0.26%
28/10722 • 4 years
|
0.22%
12/5360 • 4 years
|
0.24%
13/5359 • 4 years
|
0.22%
12/5360 • 4 years
|
0.28%
15/5363 • 4 years
|
|
Vascular disorders
Peripheral artery disease
|
0.16%
17/10719 • 4 years
|
0.18%
19/10723 • 4 years
|
0.15%
16/10720 • 4 years
|
0.19%
20/10722 • 4 years
|
0.13%
7/5360 • 4 years
|
0.19%
10/5359 • 4 years
|
0.17%
9/5360 • 4 years
|
0.19%
10/5363 • 4 years
|
|
Vascular disorders
Major cardiovascular events
|
2.4%
255/10719 • 4 years
|
2.8%
304/10723 • 4 years
|
2.6%
274/10720 • 4 years
|
2.7%
285/10722 • 4 years
|
2.4%
127/5360 • 4 years
|
2.4%
128/5359 • 4 years
|
2.7%
147/5360 • 4 years
|
2.9%
157/5363 • 4 years
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Invasive Cancer of any type
|
5.1%
550/10719 • 4 years
|
4.7%
503/10723 • 4 years
|
4.8%
518/10720 • 4 years
|
5.0%
535/10722 • 4 years
|
5.3%
283/5360 • 4 years
|
5.0%
267/5359 • 4 years
|
4.4%
235/5360 • 4 years
|
5.0%
268/5363 • 4 years
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer (in women)
|
0.92%
99/10719 • 4 years
|
0.76%
81/10723 • 4 years
|
0.87%
93/10720 • 4 years
|
0.81%
87/10722 • 4 years
|
1.0%
54/5360 • 4 years
|
0.84%
45/5359 • 4 years
|
0.73%
39/5360 • 4 years
|
0.78%
42/5363 • 4 years
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer (in men)
|
1.1%
113/10719 • 4 years
|
0.87%
93/10723 • 4 years
|
0.87%
93/10720 • 4 years
|
1.1%
113/10722 • 4 years
|
1.0%
54/5360 • 4 years
|
1.1%
59/5359 • 4 years
|
0.73%
39/5360 • 4 years
|
1.0%
54/5363 • 4 years
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer
|
0.46%
49/10719 • 4 years
|
0.54%
58/10723 • 4 years
|
0.38%
41/10720 • 4 years
|
0.62%
66/10722 • 4 years
|
0.34%
18/5360 • 4 years
|
0.58%
31/5359 • 4 years
|
0.43%
23/5360 • 4 years
|
0.65%
35/5363 • 4 years
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanoma
|
0.36%
39/10719 • 4 years
|
0.33%
35/10723 • 4 years
|
0.32%
34/10720 • 4 years
|
0.37%
40/10722 • 4 years
|
0.37%
20/5360 • 4 years
|
0.35%
19/5359 • 4 years
|
0.26%
14/5360 • 4 years
|
0.39%
21/5363 • 4 years
|
|
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Death from cancer
|
1.1%
116/10719 • 4 years
|
1.0%
109/10723 • 4 years
|
1.1%
116/10720 • 4 years
|
1.0%
109/10722 • 4 years
|
1.1%
58/5360 • 4 years
|
1.1%
58/5359 • 4 years
|
1.1%
58/5360 • 4 years
|
0.95%
51/5363 • 4 years
|
|
Blood and lymphatic system disorders
Gastrointestinal bleeding
|
4.7%
507/10719 • 4 years
|
4.7%
507/10723 • 4 years
|
5.1%
544/10720 • 4 years
|
4.4%
470/10722 • 4 years
|
5.1%
272/5360 • 4 years
|
4.4%
235/5359 • 4 years
|
5.1%
272/5360 • 4 years
|
4.4%
235/5363 • 4 years
|
Other adverse events
| Measure |
Active Cocoa Extract
n=10719 participants at risk
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
|
Placebo Cocoa Extract
n=10723 participants at risk
Cocoa extract placebo, 2 capsules/day
|
Active Multivitamin
n=10720 participants at risk
Multivitamin, 1 tablet/day
|
Placebo Multivitamin
n=10722 participants at risk
Multivitamin placebo, 1 tablet/day
|
Active Cocoa Extract + Active Multivitamin
n=5360 participants at risk
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
Multivitamin: Multivitamin, 1 tablet/day
|
Active Cocoa Extract + Placebo Multivitamin
n=5359 participants at risk
Cocoa extract: 2 capsules each day containing a total of 500 mg cocoa flavanols, including 80 mg (-)-epicatechin and 50 mg theobromine
Multivitamin placebo: Multivitamin placebo, 1 tablet/day
|
Placebo Cocoa Extract + Active Multivitamin
n=5360 participants at risk
Multivitamin: Multivitamin, 1 tablet/day
Cocoa extract placebo: Cocoa extract placebo, 2 capsules/day
|
Placebo Cocoa Extract + Placebo Multivitamin
n=5363 participants at risk
Cocoa extract placebo: Cocoa extract placebo, 2 capsules/day
Multivitamin placebo: Multivitamin placebo, 1 tablet/day
|
|---|---|---|---|---|---|---|---|---|
|
Gastrointestinal disorders
Stomach upset or pain
|
47.8%
5119/10719 • 4 years
|
46.5%
4984/10723 • 4 years
|
46.1%
4943/10720 • 4 years
|
48.1%
5160/10722 • 4 years
|
46.9%
2516/5360 • 4 years
|
48.6%
2603/5359 • 4 years
|
45.3%
2427/5360 • 4 years
|
47.7%
2557/5363 • 4 years
|
|
Gastrointestinal disorders
Nausea
|
36.4%
3900/10719 • 4 years
|
35.0%
3756/10723 • 4 years
|
35.7%
3827/10720 • 4 years
|
35.7%
3829/10722 • 4 years
|
36.9%
1977/5360 • 4 years
|
35.9%
1923/5359 • 4 years
|
34.5%
1850/5360 • 4 years
|
35.5%
1906/5363 • 4 years
|
|
Gastrointestinal disorders
Constipation
|
47.4%
5077/10719 • 4 years
|
48.0%
5143/10723 • 4 years
|
47.8%
5126/10720 • 4 years
|
47.5%
5094/10722 • 4 years
|
47.8%
2564/5360 • 4 years
|
46.9%
2513/5359 • 4 years
|
47.8%
2562/5360 • 4 years
|
48.1%
2581/5363 • 4 years
|
|
Gastrointestinal disorders
Diarrhea
|
52.5%
5627/10719 • 4 years
|
52.6%
5639/10723 • 4 years
|
51.5%
5521/10720 • 4 years
|
53.6%
5745/10722 • 4 years
|
51.5%
2762/5360 • 4 years
|
53.5%
2865/5359 • 4 years
|
51.5%
2759/5360 • 4 years
|
53.7%
2880/5363 • 4 years
|
|
Skin and subcutaneous tissue disorders
Skin rash
|
32.8%
3520/10719 • 4 years
|
32.4%
3476/10723 • 4 years
|
31.9%
3425/10720 • 4 years
|
33.3%
3571/10722 • 4 years
|
31.4%
1685/5360 • 4 years
|
34.2%
1835/5359 • 4 years
|
32.5%
1740/5360 • 4 years
|
32.4%
1736/5363 • 4 years
|
|
Skin and subcutaneous tissue disorders
Skin discoloration
|
21.8%
2332/10719 • 4 years
|
22.0%
2361/10723 • 4 years
|
21.4%
2294/10720 • 4 years
|
22.4%
2399/10722 • 4 years
|
21.0%
1124/5360 • 4 years
|
22.5%
1208/5359 • 4 years
|
21.8%
1170/5360 • 4 years
|
22.2%
1191/5363 • 4 years
|
|
General disorders
Fatigue or drowsiness
|
58.5%
6268/10719 • 4 years
|
58.1%
6228/10723 • 4 years
|
58.0%
6215/10720 • 4 years
|
58.6%
6281/10722 • 4 years
|
58.6%
3142/5360 • 4 years
|
58.3%
3126/5359 • 4 years
|
57.3%
3073/5360 • 4 years
|
58.8%
3155/5363 • 4 years
|
|
Infections and infestations
Flu-like symptoms
|
35.9%
3851/10719 • 4 years
|
37.5%
4022/10723 • 4 years
|
37.0%
3962/10720 • 4 years
|
36.5%
3911/10722 • 4 years
|
36.9%
1979/5360 • 4 years
|
34.9%
1872/5359 • 4 years
|
37.0%
1983/5360 • 4 years
|
38.0%
2039/5363 • 4 years
|
|
General disorders
Dizziness
|
39.1%
4195/10719 • 4 years
|
38.5%
4129/10723 • 4 years
|
38.4%
4113/10720 • 4 years
|
39.3%
4211/10722 • 4 years
|
38.7%
2075/5360 • 4 years
|
39.6%
2120/5359 • 4 years
|
38.0%
2038/5360 • 4 years
|
39.0%
2091/5363 • 4 years
|
|
Blood and lymphatic system disorders
Frequent nosebleeds
|
4.9%
524/10719 • 4 years
|
5.2%
555/10723 • 4 years
|
5.0%
533/10720 • 4 years
|
5.1%
546/10722 • 4 years
|
4.8%
258/5360 • 4 years
|
5.0%
266/5359 • 4 years
|
5.1%
275/5360 • 4 years
|
5.2%
280/5363 • 4 years
|
|
Blood and lymphatic system disorders
Easy bruising
|
35.8%
3836/10719 • 4 years
|
36.0%
3864/10723 • 4 years
|
35.0%
3756/10720 • 4 years
|
36.8%
3944/10722 • 4 years
|
35.1%
1879/5360 • 4 years
|
36.5%
1957/5359 • 4 years
|
35.0%
1877/5360 • 4 years
|
37.1%
1987/5363 • 4 years
|
|
Blood and lymphatic system disorders
Blood in urine
|
8.4%
904/10719 • 4 years
|
8.0%
863/10723 • 4 years
|
8.2%
876/10720 • 4 years
|
8.3%
891/10722 • 4 years
|
8.3%
446/5360 • 4 years
|
8.5%
458/5359 • 4 years
|
8.0%
430/5360 • 4 years
|
8.1%
433/5363 • 4 years
|
|
Nervous system disorders
Migraine
|
7.8%
834/10719 • 4 years
|
9.1%
971/10723 • 4 years
|
8.3%
887/10720 • 4 years
|
8.6%
918/10722 • 4 years
|
7.6%
409/5360 • 4 years
|
7.9%
425/5359 • 4 years
|
8.9%
478/5360 • 4 years
|
9.2%
493/5363 • 4 years
|
|
Nervous system disorders
Other headaches
|
37.4%
4010/10719 • 4 years
|
38.9%
4176/10723 • 4 years
|
37.9%
4065/10720 • 4 years
|
38.4%
4121/10722 • 4 years
|
37.4%
2007/5360 • 4 years
|
37.4%
2003/5359 • 4 years
|
38.4%
2058/5360 • 4 years
|
39.5%
2118/5363 • 4 years
|
|
General disorders
Lightheadedness
|
39.8%
4269/10719 • 4 years
|
39.5%
4231/10723 • 4 years
|
39.2%
4206/10720 • 4 years
|
40.0%
4294/10722 • 4 years
|
39.7%
2126/5360 • 4 years
|
40.0%
2143/5359 • 4 years
|
38.8%
2080/5360 • 4 years
|
40.1%
2151/5363 • 4 years
|
|
General disorders
Unintentional Fall
|
56.6%
6067/10719 • 4 years
|
56.5%
6059/10723 • 4 years
|
56.4%
6042/10720 • 4 years
|
56.7%
6084/10722 • 4 years
|
56.9%
3048/5360 • 4 years
|
56.3%
3019/5359 • 4 years
|
55.9%
2994/5360 • 4 years
|
57.2%
3065/5363 • 4 years
|
Additional Information
COSMOS Study Director
Brigham and Women's Hospital; 900 Commonwealth Ave, 3rd fl.; Boston, MA 02215
Phone: 1-800-633-6913
Email: [email protected]
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place