Vitamin D and Omega-3 Trial (VITAL)

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 will test 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 will also explore (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
of vitamin D and EPA+DHA, race/ethnicity (for vitamin D), and body mass index (for vitamin
D), as well as age, sex, sunlight exposure, calcium and phosphorus intakes, 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 take two pills each day -- one softgel that contains either
vitamin D or vitamin D placebo and one capsule that contains either omega-3 or omega-3
placebo. Participants receive their study pills in convenient calendar packages via U.S.
mail.

Participants also 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.
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 1-4 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 have a clinical exam, including measurement of
height, weight, other anthropometrics, blood pressure, and physical performance. They also
provide fasting blood and urine samples, and undergo 2-hour oral glucose tolerance testing,
lung function testing (spirometry), electrocardiograms, bone mineral density testing,
2D-echocardiography, and assessments of thinking and mood.

To be eligible for the study, respondents had to, at study entry,:

1. be men aged 50 or older or women aged 55 or older;

2. have no history of cancer (except non-melanoma skin cancer), heart attack, stroke,
transient ischemic attack, angina pectoris, CABG, or PCI;

3. 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
Wegener's granulomatosis;

4. have no allergy to fish or soy;

5. have no other serious illness that would preclude participation;

6. 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;

7. 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;

8. not be taking fish oil supplements, or, if taking, willing to forego their use during
the trial