Cognitive Decline
Conditions
Brief summary
The VITamin D and OmegA-3 TriaL (VITAL; NCT 01169259) is an ongoing randomized clinical trial in 25,875 U.S. men and women investigating whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 gram) reduces the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. This ancillary study is being conducted among participants in VITAL and will examine whether vitamin D or fish oil is associated with cognitive decline in 3000 older participants of VITAL.
Detailed description
Primary aim of annual rate of cognitive decline. Secondary aims will be addressed in sub-set of participants: 1) among participants, African-American race (African-Americans have high risk of Vitamin D deficiency) modifies effects of vitamin D3 supplementation on cognitive decline; 2) among a subset of participants, baseline plasma levels of vitamin D and omega-3 fatty acids modify agent effects.
Interventions
DIETARY_SUPPLEMENTvitamin D3
Vitamin D3 (cholecalciferol), 2000 IU per day
Omacor, 1 capsule per day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid \[EPA\] and 375 mg of docosahexaenoic acid \[DHA\]).
DIETARY_SUPPLEMENTVitamin D3 placebo
Vitamin D placebo
DIETARY_SUPPLEMENTFish oil placebo
Fish oil placebo
Sponsors
National Institute on Aging (NIA)
Brigham and Women's Hospital
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
60 Years to 92 Years
Healthy volunteers
Yes
Inclusion criteria
Participants in VITAL (NCT 01169259) who meet the following criteria are eligible to participate in this ancillary study: 1. are aged 60 or more 2. have no hearing impairment 3. indicate a willingness on the run-in phase to participate in a cognitive sub-study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Global Composite Score for Cognitive Decline | Change over two assessments (baseline, 2.8 years). | We administered by telephone, eight cognitive tests (1.Telephone Interview of Cognitive Status (TICS); 2.Delayed recall of the TICS 10-word list; 3.East Boston Memory Test (EBMT); 4.Delayed recall of the EBMT; 5.Category fluency test (animal naming test); 6.Oral Trail Making Test (OTMT-Part A); 7. OTMT-Part B; 8.Digit span backwards). The primary endpoint was the change over time (last assessment score minus the baseline assessment score) in GLOBAL COMPOSITE SCORE (average of Z-scores of component tests); for both baseline and last assessment Z-scores, a mean Z-score of 0 represents the mean and the higher the Z-score, the better the overall cognitive performance across the tests. The primary endpoint was a difference of two Z-scores, so a value of 0 means no change over time, a positive value means an increase over time and a negative value means a decrease (or decline) over time, for clinical significance, 1 year of aging is associated with a primary endpoint value of -0.004. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Episodic Memory Score for Cognitive Decline | Change over two assessments (baseline, 2.8 years) | The outcome measure was change over time (last assessment score minus the baseline assessment score) in the EPISODIC MEMORY SCORE combining z-scores of 4 tests: the immediate and delayed recalls of both the East Boston Memory Test (EBMT) and the Telephone Interview of Cognitive Status (TICS) 10-word list; for both baseline and last assessment Z-scores, a mean Z-score of 0 represents the mean and the higher the Z-score, the better the overall cognitive performance across the tests. The primary endpoint was a difference of two Z-scores, so a value of 0 means no change over time, a positive value means an increase over time and a negative value means a decrease (or decline) over time, for clinical significance, 1 year of aging is associated with a primary endpoint value of -0.01. |
| Change in Executive Function Score for Cognitive Decline | Change over two assessments (baseline, 2.8 years) | The outcome measure is change over time (last assessment score minus the baseline assessment score) in the EXECUTIVE FUNCTION SCORE combining z-scores of 4 tests: category fluency (animal naming), digit span backwards, and Oral Trails Making Test (OTMT)-Part A and OTMT-Part B; for both baseline and last assessment Z-scores, a mean Z-score of 0 represents the mean and the higher the Z-score, the better the overall cognitive performance across the tests. The primary endpoint was a difference of two Z-scores, so a value of 0 means no change over time, a positive value means an increase over time and a negative value means a decrease (or decline) over time, for clinical significance, 1 year of aging is associated with a primary endpoint value of +0.006. |
| Change in Telephone Interview of Cognitive Status (TICS) for Cognitive Decline. | Change over two assessments (baseline, 2.8 years) | Change over time (last assessment score minus the baseline assessment score) on the TICS (0-41 points), a measure of general cognition. A higher value on the TICS represents better cognitive performance; for clinical significance, 1 year of aging is associated with a primary endpoint value of -0.05 |
Countries
United States
Participant flow
Pre-assignment details
In this telephone interview ancillary study, participants (NCT01169259) who:1) were aged 60 or more; 2) had no hearing impairment; 3) were willing to participate in a cognitive sub-study (during run-in phase) were included.
Participants by arm
| Arm | Count |
|---|---|
| TELEPHONE INTERVIEW ANCILLARY STUDY: ACTIVE Vitamin D + ACTIVE Omega-3 Fatty Acids ACTIVE Vitamin D = Vitamin D3, one 2000 IU capsule/day; ACTIVE Omega-3 Fatty Acids = Omacor, one 1-gram capsule/day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid \[EPA\] and 375 mg of docosahexaenoic acid \[DHA\]). | 844 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: ACTIVE Vitamin D + PLACEBO Omega-3 Fatty Acids ACTIVE Vitamin D = Vitamin D3, one 2000 IU capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day | 866 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: PLACEBO Vitamin D + ACTIVE Omega-3 Fatty Acids PLACEBO Vitamin D, one capsule/day; ACTIVE Omega-3 Fatty Acids = Omacor, one 1-gram capsule/day. Each capsule of Omacor contains 840 milligrams of marine omega-3 fatty acids (465 mg of eicosapentaenoic acid \[EPA\] and 375 mg of docosahexaenoic acid \[DHA\]). | 855 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids PLACEBO Vitamin D, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day | 859 |
| Total | 3,424 |
Baseline characteristics
| Characteristic | TELEPHONE INTERVIEW ANCILLARY STUDY: ACTIVE Vitamin D + PLACEBO Omega-3 Fatty Acids | TELEPHONE INTERVIEW ANCILLARY STUDY: PLACEBO Vitamin D + ACTIVE Omega-3 Fatty Acids | TELEPHONE INTERVIEW ANCILLARY STUDY: ACTIVE Vitamin D + ACTIVE Omega-3 Fatty Acids | TELEPHONE INTERVIEW ANCILLARY STUDY: PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 751 Participants | 767 Participants | 749 Participants | 769 Participants | 3036 Participants |
| Age, Categorical Between 18 and 65 years | 115 Participants | 88 Participants | 95 Participants | 90 Participants | 388 Participants |
| Age, Continuous | 70.8 years STANDARD_DEVIATION 5.9 | 71.1 years STANDARD_DEVIATION 6 | 71.0 years STANDARD_DEVIATION 6 | 70.7 years STANDARD_DEVIATION 5.7 | 70.9 years STANDARD_DEVIATION 5.9 |
| Race/Ethnicity, Customized African American | 209 Participants | 181 Participants | 178 Participants | 175 Participants | 743 Participants |
| Race/Ethnicity, Customized Asian/Pacific Islander | 9 Participants | 8 Participants | 16 Participants | 8 Participants | 41 Participants |
| Race/Ethnicity, Customized Hispanic (not African American) | 19 Participants | 13 Participants | 12 Participants | 17 Participants | 61 Participants |
| Race/Ethnicity, Customized Native American/Alaskan Native | 14 Participants | 14 Participants | 20 Participants | 25 Participants | 73 Participants |
| Race/Ethnicity, Customized Non-Hispanic white | 589 Participants | 624 Participants | 595 Participants | 621 Participants | 2429 Participants |
| Race/Ethnicity, Customized Other/unknown | 26 Participants | 15 Participants | 23 Participants | 13 Participants | 77 Participants |
| Region of Enrollment United States | 866 participants | 855 participants | 844 participants | 859 participants | 4218 participants |
| Sex: Female, Male Female | 527 Participants | 503 Participants | 484 Participants | 502 Participants | 2016 Participants |
| Sex: Female, Male Male | 339 Participants | 352 Participants | 360 Participants | 357 Participants | 1408 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk |
|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 41 / 1,710 | 26 / 1,714 | 42 / 1,699 | 25 / 1,725 | 26 / 844 | 15 / 866 | 16 / 855 | 10 / 859 |
| other Total, other adverse events | 1,259 / 1,710 | 1,236 / 1,714 | 1,220 / 1,699 | 1,275 / 1,725 | 600 / 844 | 659 / 866 | 620 / 855 | 616 / 859 |
| serious Total, serious adverse events | 138 / 1,710 | 117 / 1,714 | 134 / 1,699 | 121 / 1,725 | 74 / 844 | 64 / 866 | 60 / 855 | 57 / 859 |
Outcome results
Primary
Change in Global Composite Score for Cognitive Decline
We administered by telephone, eight cognitive tests (1.Telephone Interview of Cognitive Status (TICS); 2.Delayed recall of the TICS 10-word list; 3.East Boston Memory Test (EBMT); 4.Delayed recall of the EBMT; 5.Category fluency test (animal naming test); 6.Oral Trail Making Test (OTMT-Part A); 7. OTMT-Part B; 8.Digit span backwards). The primary endpoint was the change over time (last assessment score minus the baseline assessment score) in GLOBAL COMPOSITE SCORE (average of Z-scores of component tests); for both baseline and last assessment Z-scores, a mean Z-score of 0 represents the mean and the higher the Z-score, the better the overall cognitive performance across the tests. The primary endpoint was a difference of two Z-scores, so a value of 0 means no change over time, a positive value means an increase over time and a negative value means a decrease (or decline) over time, for clinical significance, 1 year of aging is associated with a primary endpoint value of -0.004.
Time frame: Change over two assessments (baseline, 2.8 years).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Vitamin D | Change in Global Composite Score for Cognitive Decline | -0.24 Z-score | Standard Error 0.01 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Vitamin D Placebo | Change in Global Composite Score for Cognitive Decline | -0.25 Z-score | Standard Error 0.01 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Omega-3 Fatty Acids | Change in Global Composite Score for Cognitive Decline | -0.25 Z-score | Standard Error 0.01 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Omega-3 Fatty Acids Placebo | Change in Global Composite Score for Cognitive Decline | -0.24 Z-score | Standard Error 0.01 |
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in vitamin D active group minus the rate in placebo group). A mixed model included terms for the variables time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization).p-value: 0.3195% CI: [-0.01, 0.02]Mixed Models Analysis
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in omega-3 fatty acids active group minus the rate in placebo group). A mixed model included the variables, time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization).p-value: 0.1495% CI: [-0.02, 0.003]Mixed Models Analysis
Secondary
Change in Episodic Memory Score for Cognitive Decline
The outcome measure was change over time (last assessment score minus the baseline assessment score) in the EPISODIC MEMORY SCORE combining z-scores of 4 tests: the immediate and delayed recalls of both the East Boston Memory Test (EBMT) and the Telephone Interview of Cognitive Status (TICS) 10-word list; for both baseline and last assessment Z-scores, a mean Z-score of 0 represents the mean and the higher the Z-score, the better the overall cognitive performance across the tests. The primary endpoint was a difference of two Z-scores, so a value of 0 means no change over time, a positive value means an increase over time and a negative value means a decrease (or decline) over time, for clinical significance, 1 year of aging is associated with a primary endpoint value of -0.01.
Time frame: Change over two assessments (baseline, 2.8 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Vitamin D | Change in Episodic Memory Score for Cognitive Decline | 0.00 Z-score | Standard Error 0.02 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Vitamin D Placebo | Change in Episodic Memory Score for Cognitive Decline | -0.02 Z-score | Standard Error 0.02 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Omega-3 Fatty Acids | Change in Episodic Memory Score for Cognitive Decline | -0.03 Z-score | Standard Error 0.02 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Omega-3 Fatty Acids Placebo | Change in Episodic Memory Score for Cognitive Decline | 0.02 Z-score | Standard Error 0.02 |
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in vitamin D active group minus the rate in placebo group). A mixed model included the variables, time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization).p-value: 0.4995% CI: [-0.01, 0.03]Mixed Models Analysis
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in omega-3 active group minus the rate in placebo group). A mixed model included the variables, time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization).p-value: 0.0395% CI: [-0.04, -0.002]Mixed Models Analysis
Secondary
Change in Executive Function Score for Cognitive Decline
The outcome measure is change over time (last assessment score minus the baseline assessment score) in the EXECUTIVE FUNCTION SCORE combining z-scores of 4 tests: category fluency (animal naming), digit span backwards, and Oral Trails Making Test (OTMT)-Part A and OTMT-Part B; for both baseline and last assessment Z-scores, a mean Z-score of 0 represents the mean and the higher the Z-score, the better the overall cognitive performance across the tests. The primary endpoint was a difference of two Z-scores, so a value of 0 means no change over time, a positive value means an increase over time and a negative value means a decrease (or decline) over time, for clinical significance, 1 year of aging is associated with a primary endpoint value of +0.006.
Time frame: Change over two assessments (baseline, 2.8 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Vitamin D | Change in Executive Function Score for Cognitive Decline | -0.48 Z-score | Standard Error 0.02 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Vitamin D Placebo | Change in Executive Function Score for Cognitive Decline | -0.48 Z-score | Standard Error 0.02 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Omega-3 Fatty Acids | Change in Executive Function Score for Cognitive Decline | -0.47 Z-score | Standard Error 0.02 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Omega-3 Fatty Acids Placebo | Change in Executive Function Score for Cognitive Decline | -0.49 Z-score | Standard Error 0.02 |
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in vitamin D active group minus the rate in placebo group). A mixed model included terms for the variables time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization).p-value: 0.2395% CI: [-0.01, 0.02]Mixed Models Analysis
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in omega-3 active group minus the rate in placebo group). A mixed model included terms for the variables time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization)p-value: 0.6895% CI: [-0.01, 0.02]Mixed Models Analysis
Secondary
Change in Telephone Interview of Cognitive Status (TICS) for Cognitive Decline.
Change over time (last assessment score minus the baseline assessment score) on the TICS (0-41 points), a measure of general cognition. A higher value on the TICS represents better cognitive performance; for clinical significance, 1 year of aging is associated with a primary endpoint value of -0.05
Time frame: Change over two assessments (baseline, 2.8 years)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Vitamin D | Change in Telephone Interview of Cognitive Status (TICS) for Cognitive Decline. | 0.12 score on a scale | Standard Error 0.07 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Vitamin D Placebo | Change in Telephone Interview of Cognitive Status (TICS) for Cognitive Decline. | 0.07 score on a scale | Standard Error 0.07 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Active Omega-3 Fatty Acids | Change in Telephone Interview of Cognitive Status (TICS) for Cognitive Decline. | 0.005 score on a scale | Standard Error 0.07 |
| TELEPHONE INTERVIEW ANCILLARY STUDY: Omega-3 Fatty Acids Placebo | Change in Telephone Interview of Cognitive Status (TICS) for Cognitive Decline. | 0.18 score on a scale | Standard Error 0.07 |
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in vitamin D active group minus the rate in placebo group). A mixed model included the variables, time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization).p-value: 0.4695% CI: [-0.04, 0.09]Mixed Models Analysis
Comparison: The rates of cognitive decline over 2.8 years were compared in the two groups (rate in omega-3 active group minus the rate in placebo group). A mixed model included the variables, time since randomization, assignment to one arm, assignment to the other arm, sex, age, race/ethnicity, history of depression and the six interaction terms (products with time since randomization).p-value: 0.00395% CI: [-0.17, -0.04]Mixed Models Analysis