Micronutrients

All Drugs and Chemicals

Bone Density Conservation Agents

Other Dietary Supplements

Vitamins

Vitamin D

Cholecalciferol

Ergocalciferols

Trace Elements

Hormones

Calcium

Calcium, Dietary

Omega 3 Fatty Acid

Vitamin D3

Calciferol

Ergocalciferol

Vitamin D2

Vitamin D3 (cholecalciferol), 2000 IU per day.

vitamin D3

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 \[DHA\]).

omega-3 fatty acids (fish oil)

Vitamin D3 placebo

Fish oil placebo

JoAnn E. Manson, MD, DrPH

Julie E. Buring, ScD

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.

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.

Vitamin D and Omega-3 Trial (VITAL)

Researchers who are interested in collaborating on research that uses VITAL data should visit the "For VITAL Investigators" section of the VITAL website, www.vitalstudy.org.

Death from invasive cancer of any type, excluding first 2 years of follow-up

Death from any cause, excluding first 2 years of follow-up

Total coronary heart disease = a composite of myocardial infarction, coronary revascularization (percutaneous coronary intervention or coronary-artery bypass grafting), and death from coronary heart disease

Myocardial infarction, excluding first 2 years of follow-up

tubular, tubulovillous, villous adenoma; adenoma w/high-grade dysplasia

hyperplastic polyp, traditional serrated adenoma, sessile serrated polyp

Major cardiovascular event = a composite endpoint of myocardial infarction, stroke, and death from cardiovascular causes

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)

Invasive cancer of any type, 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

National Cancer Institute (NCI)

National Heart, Lung, and Blood Institute (NHLBI)

Office of Dietary Supplements (ODS)

National Institute of Neurological Disorders and Stroke (NINDS)

National Center for Complementary and Integrative Health (NCCIH)

Pharmavite LLC

Pronova BioPharma

BASF

Brigham and Women's Hospital

Principal Investigator

Vit D Monitored safety cond'ns: hypercalcemia, kidney stones, parathyroid disease, kidney failure or dialysis; Other symptoms, side effects: GI bleeding, easy bruising; stomach upset or pain; nausea; constipation, diarrhea, skin rash

Omega-3 FA Monitored safety cond'ns: GI bleeding; blood in urine; easy bruising; freq nosebleeds; kidney failure or dialysis; Other symptoms, side effects: stomach upset or pain; nausea; constipation; diarrhea; skin rash; bad taste in mouth; increased burping

Active Vitamin D

Vitamin D Placebo

Omacor, one 1-g capsule/day. Each capsule of Omacor contains 840 mg of marine omega-3 fatty acids (465 mg of EPA + 375 mg of DHA).

Active Omega-3 Fatty Acids

Omega-3 fatty acids placebo, one capsule/day

Omega-3 Fatty Acids Placebo

Vitamin D3 (one 2000 IU capsule/day) + Omacor, one 1-g capsule/day. Each capsule of Omacor contains 840 mg of marine omega-3 fatty acids (465 mg of EPA + 375 mg of DHA).

Active Vitamin D/Active Omega-3 Fatty Acids

Vitamin D3, one 2000 IU capsule/day + Omega-3 fatty acids placebo, one capsule/day

Active Vitamin D/Placebo Omega-3 Fatty Acids

Vitamin D placebo, one capsule/day + Omacor, one 1-g capsule/day. Each capsule of Omacor contains 840 mg of marine omega-3 fatty acids (465 mg of EPA + 375 mg of DHA).

Placebo Vitamin D/Active Omega-3 Fatty Acids

Vitamin D placebo, one capsule/day + Omega-3 fatty acids placebo, one capsule/day

Placebo Vitamin D/Placebo 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 \[DHA\]).

ACTIVE Vitamin D + ACTIVE Omega-3 Fatty Acids

ACTIVE Vitamin D = Vitamin D3, one 2000 IU capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day

ACTIVE Vitamin D + PLACEBO 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 \[DHA\]).

PLACEBO Vitamin D + ACTIVE Omega-3 Fatty Acids

PLACEBO Vitamin D, one capsule/day; PLACEBO Omega-3 Fatty Acids, one capsule/day

PLACEBO Vitamin D + PLACEBO Omega-3 Fatty Acids

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Non-Hispanic white

African American

Hispanic (not African American)

Asian/Pacific Islander

Native American/Alaskan Native

Other/unknown

Not all participants reported race/ethnicity

Spots Global Cancer Trial Database for fish oil placebo