Vitamin D and Omega-3 Trial (VITAL)

Study Overview
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Brief Summary
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The VITamin D and OmegA-3 TriaL (VITAL) is a randomized clinical trial in 25,871 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. The 5-year intervention phase (study pill-taking, median 5.3 years) has ended; post-intervention observational follow-up of study participants is ongoing.

Detailed Description
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The VITamin D and OmegA-3 TriaL (VITAL) is a randomized clinical trial of vitamin D (in the form of vitamin D3 [cholecalciferol]) and marine omega-3 fatty acid (eicosapentaenoic acid [EPA] + docosahexaenoic acid [DHA]) supplements in the primary prevention of cancer and cardiovascular disease (CVD). Existing data from laboratory studies, epidemiologic research, small primary prevention trials, and/or large secondary prevention trials strongly suggest that these nutritional agents may reduce risk for cancer or CVD, but large primary prevention trials with adequate dosing in general populations are lacking. VITAL tested the independent effects of vitamin D and omega-3 fatty acid supplementation on risk for developing cancer and CVD (primary, secondary, and other outcomes are specified in the Outcome Measures section). VITAL also explored (a) whether vitamin D and omega-3 fatty acid supplements exhibit synergistic or additive effects on cancer and CVD risk and (b) whether the effect of each supplement on cancer and CVD risk varies by baseline blood levels or intake of vitamin D and EPA+DHA, race/ethnicity, and body mass index (for vitamin D), as well as age, sex, sunlight exposure, calcium intake, and baseline risk factors for cancer and CVD. Eligible participants were assigned by chance (like a coin toss) to one of four groups: (1) daily vitamin D and omega-3; (2) daily vitamin D and omega-3 placebo; (3) daily vitamin D placebo and omega-3; or (4) daily vitamin D placebo and omega-3 placebo. Participants had an equal chance of being assigned to any of these four groups and a 3 out of 4 chance of getting at least one active agent. Participants in all groups took two pills each day -- one softgel that contained either vitamin D or vitamin D placebo and one capsule that contained either omega-3 or omega-3 placebo. Participants received their study pills in convenient calendar packages via U.S. mail. Participants fill out a short (15-20 minute) questionnaire each year. The questionnaire asks about health; lifestyle habits such as physical exercise, diet, and smoking; use of medications and dietary supplements; family history of illness, and new medical diagnoses. We request consent for medical record review to confirm endpoints. Occasionally, participants may receive a phone call from study staff to collect information or to clarify responses on the questionnaire. At baseline, 16,954 VITAL participants provided an optional blood sample. Approximately 6,000 of these participants provided a follow-up blood sample during years 1-5 of the trial. At baseline, year 2, and year 4 of the trial, a subcohort of 1,054 VITAL participants living within driving distance of Boston, Massachusetts received detailed in-clinic health assessments at the Clinical and Translational Science Center (CTSC) of Brigham and Women's Hospital. During CTSC visits, participants had a clinical exam, including measurement of height, weight, other anthropometrics, blood pressure, and physical performance. They also provided fasting blood and urine samples, and underwent 2-hour oral glucose tolerance testing, lung function testing (spirometry), electrocardiograms, bone mineral density testing, 2D-echocardiography, and assessments of thinking and mood. VITAL is supported by funding from the National Cancer Institute, National Heart, Lung and Blood Institute, Office of Dietary Supplements, National Institute of Neurological Disorders and Stroke, and the National Center for Complementary and Integrative Health. Pharmavite LLC of Northridge, California (vitamin D) and Pronova BioPharma (BASF) of Norway (Omacor® fish oil) donated the study agents, matching placebos, and packaging in the form of calendar packs.

Official Title
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Vitamin D and Omega-3 Trial (VITAL)

Conditions
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Cancer, Cardiovascular Disease

Intervention / Treatment
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* Dietary Supplement: vitamin D3
* Drug: omega-3 fatty acids (fish oil)
* Dietary Supplement: Vitamin D3 placebo
* Dietary Supplement: Fish oil placebo


Participation Criteria
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Eligibility Criteria
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To be eligible for the study, respondents had to, at study entry,: be men aged 50 or older or women aged 55 or older; have no history of cancer (except non-melanoma skin cancer), heart attack, stroke, transient ischemic attack, angina pectoris, coronary-artery bypass grafting, or percutaneous coronary intervention; have none of the following safety exclusions: history of renal failure or dialysis, hypercalcemia, hypo- or hyperparathyroidism, severe liver disease (cirrhosis), or sarcoidosis or other granulomatous diseases such as active chronic tuberculosis or granulomatosis with polyangiitis (Wegener's); have no allergy to fish or soy; have no other serious illness that would preclude participation; be consuming no more than 800 IU of vitamin D from all supplemental sources combined (individual vitamin D supplements, calcium+vitamin D supplements, medications with vitamin D [e.g., Fosamax Plus D], and multivitamins), or, if taking, willing to decrease or forego such use during the trial; be consuming no more than 1200 mg/d of calcium from all supplemental sources combined, or, if taking, willing to decrease or forego such use during the trial; not be taking fish oil supplements, or, if taking, willing to forego their use during the trial

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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Accepts Healthy Volunteers

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 D3<br>* Vitamin D3 (cholecalciferol), 2000 IU per day.<br>* Other names: cholecalciferol;Drug: omega-3 fatty acids (fish oil)<br>* Omacor, one 1-gram 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 D3<br>* Vitamin D3 (cholecalciferol), 2000 IU per day.<br>* Other names: cholecalciferol;Dietary Supplement: Fish oil placebo<br>* Fish oil placebo<br>|
| Active Comparator: Vitamin D placebo + fish oil<br> | Drug: omega-3 fatty acids (fish oil)<br>* Omacor, one 1-gram 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 D3 placebo<br>* Vitamin D placebo<br>|
| Placebo Comparator: Vitamin D placebo + fish oil placebo<br> | Dietary Supplement: Vitamin D3 placebo<br>* Vitamin D placebo<br>Dietary Supplement: 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 Invasive Cancer of Any Type | Invasive cancer of any type | 5 years | 
| Number of Participants With a Major Cardiovascular Event | Major cardiovascular event = a composite endpoint of myocardial infarction, stroke, and death from cardiovascular causes | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Died From Invasive Cancer of Any Type | Death from invasive cancer of any type | 5 years | 
| Number of Female Participants With Breast Cancer | Breast cancer (in women) | 5 years | 
| Number of Male Participants With Prostate Cancer | Prostate cancer (in men) | 5 years | 
| Number of Participants With Colorectal Cancer | Colorectal cancer | 5 years | 
| Number of Participants With Cardiovascular Event in Expanded Composite Cardiovascular Endpoint | Expanded composite cardiovascular endpoint = a composite endpoint of myocardial infarction, stroke, death from cardiovascular causes, and coronary revascularization (coronary artery bypass grafting or percutaneous coronary intervention) | 5 years | 
| Number of Participants With Myocardial Infarction | Myocardial infarction | 5 years | 
| Number of Participants With Stroke | Stroke | 5 years | 
| Number of Participants Who Died From Cardiovascular Causes | Death from cardiovascular causes | 5 years | 
| Number of Participants Who Died From Any Cause | Death from any cause | 5 years | 
| Number of Participants With Invasive Cancer of Any Type, Excluding First 2 Years of Follow-up | Invasive cancer of any type, excluding first 2 years of follow-up | 5 years, excluding first 2 years of follow-up | 
| Number of Participants With a Major Cardiovascular Event, Excluding First 2 Years of Follow-up | Major cardiovascular event = a composite endpoint of myocardial infarction, stroke, and death from cardiovascular causes; excluding first 2 years of follow-up | 5 years, excluding first 2 years of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vitamin D3, omega-3 fatty acids, fish oil, cardiovascular disease, cancer, primary prevention