Effects of Vitamin D and Omega-3 on Cerebrovascular Disease

Study Overview
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Brief Summary
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The VITamin D and OmegA-3 TriaL (VITAL; NCT 01169259) is a completed randomized clinical trial in 25,875 U.S. men and women which investigated whether taking daily dietary supplements of vitamin D3 (2000 IU) or omega-3 fatty acids (Omacor® fish oil, 1 gram) reduced the risk of developing cancer, heart disease, and stroke in people who do not have a prior history of these illnesses. Observational follow-up of participants is currently ongoing. The current study is being conducted among participants in VITAL who experience a stroke event during follow-up and will examine whether vitamin D or omega-3 fatty acid supplementation impact post-stroke outcomes.

Detailed Description
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Stroke is a leading cause of disability and death worldwide and is expected to become an even more prevalent cause of disability in the future as the population ages. Understanding risk factors which may prospectively influence stroke outcomes may help to reduce the morbidity burden of stroke. The VITamin D and OmegA-3 TriaL (VITAL) examined the impact of vitamin D3 (2,000 IU/day cholecalciferol) and omega-3 fatty acids (840 mg eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) on stroke incidence. However, the parent trial did not examine the impact of these supplements on stroke outcomes. Even if they do not significantly reduce stroke incidence, these supplements may still reduce stroke severity and improve outcomes post-stroke. Given the high morbidity burden of stroke, the impact of these supplements on stroke outcomes is of substantial scientific and public health importance. The first aim of this study is to test whether vitamin D3 or omega-3 fatty acid supplementation reduces the risk of poor functional outcomes as measured at hospital discharge and 6- and 12-months post-stroke. The second aim is to determine whether chronic cerebrovascular changes (white matter hyperintensity volume and cerebral microbleeds) mediate the effect of vitamin D3 or omega-3 fatty acid supplementation on stroke outcomes. Individuals enrolled in VITAL who experience a non-fatal stroke event will be mailed additional questionnaires assessing functional limitations, physical disability, and social disability. Responses from these questionnaires will be used to determine the effect of vitamin D3 or omega-3 fatty acid supplementation on post-stroke outcomes.

Official Title
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Effects of Vitamin D and Omega-3 on Cerebrovascular Disease

Conditions
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Stroke, Vitamin D

Intervention / Treatment
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* Dietary Supplement: Vitamin D
* Drug: Fish oil
* Dietary Supplement: Vitamin D placebo
* Drug: Fish oil placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants eligible and willing to participate in the main VITAL trial (NCT 01169259) who experience a stroke during follow-up. Exclusion Criteria: Participants eligible and willing to participate in the main VITAL trial (NCT 01169259) who do not experience a stroke during follow-up.

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Vitamin D + fish oil<br> | Dietary Supplement: Vitamin D<br>* Dietary Supplement: Vitamin D-3 (cholecalciferol), 2000 IU Other Name: cholecalciferol<br>Drug: Fish oil<br>* Drug: Omega-3 fatty acids (fish oil) 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])<br>|
| Active Comparator: Vitamin D + fish oil placebo<br> | Dietary Supplement: Vitamin D<br>* Dietary Supplement: Vitamin D-3 (cholecalciferol), 2000 IU Other Name: cholecalciferol<br>Drug: Fish oil placebo<br>* Fish oil placebo<br>|
| Active Comparator: Vitamin D placebo + fish oil<br> | Drug: Fish oil<br>* Drug: Omega-3 fatty acids (fish oil) 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])<br>Dietary Supplement: Vitamin D placebo<br>* Vitamin D placebo<br>|
| Placebo Comparator: Vitamin D placebo + fish oil placebo<br> | Dietary Supplement: Vitamin D placebo<br>* Vitamin D placebo<br>Drug: Fish oil placebo<br>* Fish oil placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Poor Stroke Outcome at Hospital Discharge as Measured by the Modified Rankin Scale (mR 3-6) | modified Rankin Scale (mRS) at hospital discharge The mRS is often seen as a measure of disability or a global health index due to its strong emphasis on mobility although it claims to be a measure of handicap. The mRS is a seven-point scale (0=no symptoms at all; 1=no significant disability despite symptoms; 2=slight disability; 3=moderate disability; 4=moderately severe disability; 5=severe disability; 6=death). To avoid issues with model convergence due to sparse data, I will a priori categorize the mRS into good (mRS 0-2) versus poor (mRS 3-6) outcomes. These data were collected during the parent study (NCT01169259) | 1 day | 
| Number of Participants With at Least One Functional Limitation After Stroke According to the Scale Adapted From Nagi | Functional limitations will be assessed through self-report using the physical performance scale adapted from Nagi. The adapted Nagi scale asks respondents if they experience any limitations in each of the following items: pulling or pushing large objects; stooping, crouching, or kneeling; reaching or extending arms above shoulder level; reaching or extending arms below shoulder level; writing or handling or fingering small objects; standing in one place for long periods; and sitting for an hour. Participants reporting a limitation in any of these items will be considered to have at least one functional limitation after stroke. | 1 year | 
| Number of Participants With a Physical Disability After Stroke as Measured by the Modified Katz Activities of Daily Living (ADL) Scale | The modified Katz ADL scale ask participants to self-report if they need needing help with any of the following items: bathing; dressing; eating; getting in and out of a chair; and walking 50 yards. Individuals who report needing help with any of those items will be considered to have a physical disability after stroke. | 1 year | 
| Number of Participants With a Physical Disability After Stroke as Measured by the Rosow-Breslau Functional Health Scale | The Rosow-Breslau Functional Health Scale asks participants to self-report if they need help with any of the following tasks: walking 0.5 mile; walking up and down stairs to the second floor; and doing heavy work around the house. Individuals who report needing help with any of those tasks will be considered to have a physical disability after stroke. | 1 year | 
| Number of Participants With Social Disability After Stroke as Measured by FHS Social Disability Scale | Social disability was assessed through a self-administered questionnaire which asked questions about social functioning developed in the Framingham Heart Study. The scale covers five social areas (housekeeping, transportation, social interaction, food preparation, and grocery shopping). Respondents are grouped into four categories (need met, no apparent problem (best outcome); need met, potential problem; uncertain need met, potential problem; need unmet, current problem (worst outcome)) for each social area using a previously published algorithm. We created summary indices for the total number of unmet needs across all areas and for the total number of unmet needs or uncertain needs met, potential problem. These indices range from 0 to 5, but to avoid problems with model convergence due to sparse data, we will a priori categorize them as 0 (best outcome), 1, or ≥2 (worst outcome). | 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, stroke outcomes, vitamin D, omega-3 fatty acid